Natural Cures For Prostate Cancer

The 21 Day Prostate Fix

21 Day Prostate Fix written by Radu Belasco is a healthier alternative to drugs and invasive medical procedures. Radu Belasco is an early prostate problem sufferer, with a family history of prostate pain, problems and cancer. Using a unique system of natural remedies, he fixed his prostate problems and wrote them in his smash hit eBook The 21 Day Prostate Fix. It is about miraculous herbs and fruits from all over the world. These unique foods have the power to cure your prostates inflammation in record time and shrink it to a healthier size. Also, you will learn how to concoct the miracle elixir that will not just cleanse your prostate, but also burn body fat. Aside from these, youll get topnotch information on nutrition, so you can keep your prostate healthy and your sex drive at its peak. Plus, youll learn other health conditions that might be contributing to your prostate issues, so you can also remedy them and get your body in its best shape ever.

The 21 Day Prostate Fix Overview

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Prostate Cancer Stem Cells A Target for New Therapies

1.1 Prostate Cancer Therapy A Historical View 156 2 Transgenic Mouse Models of Prostate Cancer 157 3 Prostate Cancer A Disease of Epithelial Differentiation 157 5 Definition of the Stem Cell Phenotype in Prostate 159 6 The Origins of Prostate Cancer 161 7 Isolation of Prostate Cancer Stem Cells 163 8 Gene Expression in Prostate Cancer Stem Cells 167 9 Implications for Prostate Cancer Therapy 170 Abstract. Prostate cancer is now a common disease in men over 50 years of age. Medical therapies for prostate cancer are based on discoveries from the mid-twentieth century, and in the long term are rarely curative. Most treatments are directed towards an androgen receptor-expressing, highly proliferative target cell, which does indeed form the vast majority of cells in a prostate tumour. However, by invoking the existence of a cancer stem cell which, like normal epithelial stem cells in the prostate, does not express androgen receptor and is relatively quiescent, the observed resistance to...

Screening for Prostate Cancer What Was the Current PSA

While entering prostate specific antigen (PSA) results into the tumor marker database, a clinical laboratory scientist noted that James Braun, age 58, had previous results at yearly intervals since age 55. The values had remained stable in the range of 3.2 to 3.4 ng mL (reference range, 2.0 to 4.0 ng mL) until this past year, when a value of 4.2 ng mL was determined 6 months ago. The CLS recalled that generally PSA is analyzed every 12 months. Did his current PSA of 4.2 ng mL indicate prostatic cancer she wondered.

Tumor Markers for the Prostate

Prostate specific antigen (PSA) is a tumor marker for prostatic carcinoma. The perfect tumor marker would be highly specific to a particular tumor within a specific tissue, be released into blood or urine for ease of analysis, provide body fluid levels that correlate with amount of tumor cells or malignancy, have potential for detection prior to overt symptoms or in early stages, have a short half-life so that changes reflect response to therapy, and have the ability to be assessed with near 100 sensitivity and specificity. Prostatic acid phosphatase (PAP) meets some of those requirements but falls short in sensitivity. Prostate specific antigen meets nearly all these requirements in detecting prostatic cancer.28 However, it is also released into blood and body fluids when the prostate is inflamed and enlarged, the condition known as prostatism. Prostatic specific antigen and prostatic acid phos-phatase are tumor markers that are best utilized if the patient has certain risk factors...

Prostate Specific Antigen

_ granules of columnar acinar prostate cells. It is a protease with trypsin-like enzy- makes up a gland such as the up, PSA is highly antigenic and readily measured by immunoassay techniques. The pancreas or prostate first techniques for analysis of PSA were various types of immunoradiometric assay Prostate specific antigen levels may not provide enough information for staging of cancer. However, these tumor markers generally provide useful information in follow-up to treatment.33 For example, in a longitudinal study following patients undergoing treatment for prostatic cancer, very low PSA levels after 5 years indicated a high likelihood for long-term remission.34 Since so many older men are having PSA levels assessed frequently, there is a wealth of data concerning PSA, benign prostatic hyperplasia (BPH), and prostatic cancer. A recent study that involved data collected over a 20-year period concluded that recent findings show that serum PSA is statistically related only to prostate...

Other Prostate Tumor Markers

Other prostatic cancer tumor markers have been utilized in the past, including total acid phosphatase activity, total alkaline phosphatase activity, and bone fraction of alkaline phosphatase activity. These enzymes have varying degrees of tissue specificity to the prostate gland, with bone alkaline phosphatase more specific than acid phosphatase activity, which is more specific than total alkaline phosphatase activi-ty.25 Recently developed prostatic cancer tumor markers include proPSA, which is a precursor to active PSA, and prostate specific membrane antigen (PSMA). Serum concentrations of these two markers are elevated in prostate cancer and have strong ability to discriminates between cancer and BPH or no disease. Two surprising prostatic cancer tumor markers are insulin-like growth factor-1 (IGF-1) and insulinlike growth factor binding protein-3 (IGFBP-3), which are associated with increased risk for prostate cancer.39 There are also gene-based and cell-based bio-markers that are...

Prostate Enlargement Benign Prostatic Hyperplasia

The prostate gland produces the fluid that surrounds and nourishes the sperm in semen. A common condition of older men is enlargement of the prostate gland (benign prostatic hyperplasia) three-quarters of men undergo some enlargement by their seventh decade. The prostate gland surrounds the urethra just below the bladder, and enlargement of the gland constricts flow of urine out of the bladder. This results in a frequent need to urinate, a slow, diminished stream of urine, and in- ability to fully empty the bladder. Although prostate enlargement can rarely be due to a cancer in the gland, in most cases, the process is benign and the cause unknown.

Micronutrients Prostate

Impaired zinc metabolism within the prostate gland may contribute to enlargement. Supplementation may reduce gland size and improve symptoms3 Supplementation may reduce risk of enlargement and prostate cancer1 prostate gland may contribute to enlargement. Supplementation can reduce activity of these substances and may reduce gland size and improve symptoms Fig. 5.31 Vitamin E supplementation and risk of prostate cancer. 30,000 50-69-year-old Finnish men were given 50 mg day alpha-tocopherol or placebo for 5-8 years. There were 151 new cases of prostate cancer in the placebo group, compared with only 99 new cases in the treatment group. (Source The ATBC Cancer Prevention Group. N Engl J Med. 1994 330 1029)

The Anus Rectum and Prostate Multiple Choice

A 65-year-old gardener presents to the office for difficulty with urination. Increasingly, he has noticed feeling like his bladder has not emptied completely and his urinary stream has a decreased force. He experiences dribbling after he completes urination. These symptoms have been going on for several years, but his level of discomfort has increased over the past few months. On physical examination, you feel a symmetrically enlarged, smooth, and firm prostate (A) Normal prostate (B) Prostatitis (C) Benign prostatic hyperplasia (D) Prostate cancer 6. A 36-year-old computer programmer presents to the office with pain with urination, and fever. On palpation of the prostate, his gland is swollen, tender, and warm to the touch. Your most likely diagnosis is (A) Normal prostate (B) Benign prostatic hyperplasia (C) Prostate cancer (D) Prostatitis

Prostate Cancer

Prostate cancer is the most common type of cancer in North American men. The number of men affected by prostate cancer is nearly equal to the number of women affected by breast cancer, but the mortality of prostate cancer is lower (see table on page 3). ANATOMY The prostate gland is part of the male reproductive system. It makes and stores portions of the seminal fluid, a fluid that is mixed with sperm to produce semen. The gland is about the size of a walnut and is located below the bladder near the base of the penis. It surrounds the upper part of the urethra, the tube that empties urine from the bladder. Because of its location, abnormal growth of the prostate can pinch the urethra, blocking the flow of urine. The prostate gland is regulated by the male sex hormone, testosterone. RISK FACTORS Age, family history, and diet are the main risk factors. Prostate cancer usually occurs in men over the age of 55. The average age of patients at the time of diagnosis is 70. A man's risk of...

Diet Prostate

High-fat diets, particularly saturated fat from animal sources (meat, eggs, dairy products), promotes enlargement of the prostate and may also increase risk of prostate cancer.1,2 Diets high in fruits and vegetables, particularly those rich in lycopene (a carotenoid found in large amounts in tomatoes), reduce risk of prostate enlargement and cancer.1 Overactivity of certain prostaglandins within the prostate gland may contribute to enlargement. Substituting high-quality, cold-pressed plant oils for saturated fat in the diet, along with eating fresh fish two to three times per

Prostate Gland

Epidemiological studies suggested that consumption of tomato products is associated with reduced risk of prostate cancer in men. It was soon shown that there is also an association between intake of tomato products and increased levels of lycopene in human prostate (132,152), and this has been confirmed in other studies. The intake-dependent accumulation of lycopene in prostate in the rat has also been demonstrated (149). The percentage of lycopene present as cis isomers is greater in human prostate than in serum and higher in serum than in food products (132,134,153), suggesting either isomerization or preferential retention of cis isomers in tissues.

B Prostate cancer

A recently published model 18 addressed an important question what should be the initial treatment of prostate cancer in elderly men Radical prostatectomy, external beam radiation therapy, or watchful waiting The authors subclassified the cancers into three grades Gleason 2-4, 5-7, 810. Their results are shown in Figure 2. They also analyzed the impact of comorbidity on the outcome. In men with Gleason 5-7 cancer, radical prostatectomy, but not radiation therapy resulted in higher quality adjusted life expectancy (QALE) for patients with mild comorbidity up to age 75, and men with moderate comorbidity up to age 65. For aggressive disease, potentially curative therapy improves QALE in men with even moderate comorbidity up to age 75.

Loss of Anchorage Dependent Growth and Altered Cell Adhesion

Several lines of evidence implicate MMPs in tumor progression and metastasis. First, MMPs are overexpressed in tumors from a variety of tissues and the expression of one, ma-trilysin, is clearly elevated in invasive prostate cancer epithelium (34-36). Second, reduction of tissue inhibitor of matrix metalloprotein-ases-1 (TIMP-1) expression in mouse fibroblasts (Swiss 3T3), using antisense RNA technology, increased the incidence of metastatic tumors in immunocompromised mice. Similarly, overexpression of the various MMPs has provided direct evidence for their role in metastasis. Importantly, synthetic MMP inhibitors have also been produced and they lead to a reduction in metastasis in several experimental models of melanoma, colorectal carcinoma, and mammary carcinoma, suggesting a mechanism by which the invasive potential of tumors may be reduced (37).

Transcription Factors as Oncogenes

Bcl-2 is an example of a cytoplasmic oncogene that has anti-apoptotic potential. Increased production of bcl-2 protein is seen in a variety of tumor types and is associated with poor prognosis in carcinomas of the colon and prostate. The function of bcl-2 is explained in detail in the apopto-sis section of this chapter.

Phosphatase and Tensin Homologue

The phosphatase and tensin homologue (PTEN) or mutated in multiple advanced cancers (MMAC) tumor suppressor gene was first identified in the most aggressive form of brain cancer, glioblastoma multiform. PTEN also is mutated in a significant fraction of endome-trial carcinomas, prostate carcinomas, and melanomas. PTEN's primary functions as a tumor suppressor gene are the induction of cell cycle arrest and apoptosis (92). PTEN is a dual-specificity phosphatase, meaning that it can dephosphorylate proteins on serine, threonine, and tyrosine residues. It specifically de-phosphorylates PtdIns-3,4,5-P3, antagonizing the function of PI-3K. PTEN, therefore, acts as a negative regulator of Akt activation. Because Akt can suppress apoptosis by the phosphorylation of the pro-apoptotic protein Bad, PTEN can induce apoptosis of mutated or stressed cells to prevent tumor formation.

Protein Zag A New Adipokine

A dramatic weight loss, entailing a reduction of the adipose organ by up to 85 , is a characteristic feature of tumour cachexia. Several factors are implicated in this process one of them is possibly ZAG (zinc-a2-glycoprotein), a 43-kDa protein originally isolated in human plasma 102 and later described in several organs breast, prostate, liver, lung and skin 103 . Overexpression of protein ZAG occurs in several malignant tumours and is thus used as a tumour marker.

Age And Carcinogenesis

The incidence of common cancers increases with age (Figure 1). This association is universal 2 and is observed with the aging of any population around the world. A clear explanation of this phenomenon is the time-length of carcinogenesis, a stepwise process involving the activation of cellular oncogenes, and the suppression of anti-proliferative genes (anti-oncogenes)3. It is reasonable to assume that the duration of carcinogenesis reflects the number of stages involved in the pathogenesis of different tumors, and that this number be highest for tumors whose incidence peaks late in life, such as adenocarcinoma of the prostate and of the large bowel, or non-melanomatous skin cancer 3. In the era of chemoprevention and recognition and elimination of environmental carcinogens, an alternative possibility should be considered. These interventions may cause the prolongation of one or more carcinogenic steps and, in so doing they may delay the development of cancer. For example, the...

Targeting Loss of Tumor Suppressor Function and Oncogene Overexpression

Plied to introduce wild-type copies of tumor suppressor genes into malignant cells, thus potentially reversing the neoplastic pheno-type. The p53 tumor suppressor gene has been of interest because p53 mutation occurs commonly in a variety of human cancers, including breast, lung, colon, prostate, bladder, and cervix. The use of adenoviral vectors to deliver the p53 transgene to human tumors is now under evaluation in several clinical trials (145).The overexpression of Fas ligand caused by adenovirus-mediated wild-type p53 gene transfer induces neutrophil infiltration into human colorectal tumors, which may play a critical role in the bystander effect of p53 gene therapy (146).

Recommended Daily Intakes

The usual therapeutic dose range is 15-45 mg day.10 Carotene supplements derived from natural sources are preferable. They contain, along with beta-carotene, a mixture of carotenoids, including lutein, alpha-carotene, and lycopene, and may have additional health benefits. For example, ly-copene is a potent antioxidant11 and may decrease the risk of prostate cancer and cataract.

Use in Prevention and Therapy

Vitamin A is one of nature's primary anticancer substances, particularly in the skin and mucous membranes. Ample intakes of vitamin A have been shown to protect against cancers of the lung, bladder, prostate, larynx, esophagus, stomach, and colon. Vitamin A can prevent precancerous lesions, such as oral leukoplakia (white patches on the lips and mouth often found in smokers) and cervical dysplasia, from developing and may produce regression and disappearance of these disorders.15 As a cancer treatment, large doses of retinoic acid may reduce growth and recurrence of certain forms of skin cancer.16 As an antioxidant, beta-carotene helps provide protection against damage from many xenobiotics (such as polychlorinated biphenyls PCBs ). It may also reduce the risk of skin cancer associated with exposure to sunlight6 and radiation.2

Common Types Of Cancer

Some cancers, such as those affecting the brain, breasts, or prostate gland, do not have clear connections to lifestyle or the environment, but appear to be a consequence of normal physiology and cellular biochemistry. Our bodies, complex machines that they are, simply start to The deadliness of a cancer varies depending on the tissue that is affected. Prostate cancer struck more than 200,000 American men in 2003, but the mortality was only 13 percent (that is, 28,900 men died of prostate cancer in the same year). By contrast, brain tumors have a mortality of 72 percent, and lung cancer is even worse, with a mortality of 88 percent. But the deadliest of all cancers are those that appear in the pancreas, where the mortality is a numbing 98 percent (see table on page 3).

The Sarcoplasmic Endoplasmic Reticulum Ca2ATPase Pump

Carboxyamido-triazole (CAI) is one such compound. CAI has been reported to be able to inhibit the invasive behaviour of breast carcinoma cell lines in vitro. The matrix metalloproteinases associated with these cells also appear to be inhibited in parallel (Lambert et al. 1997). Not surprising, therefore, is the finding that CAI inhibits the adhesion of glioma cells to collagen type IV coated substrata and also inhibits their invasion in vitro. CAI also appears to be capable of inhibiting cell proliferation (Jacobs et al. 1997). The antiproliferation and anti-invasion properties of CAI have also been described by Wasilenko et al. (1996) using human prostate cancer cell lines. These are clear indications of the variety of downstream pathways activated by calcium influx that are inhibited by CAI. Finally, CAI has been reported to stabilise the disease in patients with a variety of refractory solid tumours (Kohn et al. 1996).

The Antigen Specificity of Naturally Arising TR

The prevailing hypothesis regarding the TCR specificity of naturally arising regulatory T cells is that they recognize self-antigen, and that this interaction is important for TR development and function to suppress autoimmunity. This model was originally prompted by two studies in the 1990s that indirectly suggested that naturally arising TR recognize tissue-specific self-antigens. Initial studies by Taguchi and colleagues suggested that the functional maintenance of CD4+ Tcellscapableofprotectionagainst prostatitisoroophoritisrequired the presence of the corresponding organ, as adoptive transfer of T cells from male mice were more effective at preventing neonatal thymectomy-induced autoimmune prostatitis than oophoritis, and vice versa for T cells from female mice (Taguchi et al. 1994). Studies from Mason's group extended this observation by demonstrating that ablation of the thyroid gland resulted in the selective functional loss of T cells within the CD4+ population capable of...

Biological Activity and Side Effects

4.3.4 Recent Developments Lipophilic An-tifolates. These compounds were designed to circumvent resistance to methotrexate that arises by reduced folate uptake or reduced polyglutamylation. They are relatively lipophilic compounds, lacking a glutamate residue, that get into cells by passive diffusion. The first examples to receive clinical evaluation were trimetrexate (70) and piritrexim (71). Trimetrexate was superior to metho-trexate in animal models, with activity in methotrexate-resistantlines (298) but (unlike methotrexate) is susceptible to P-glycopro-tein-mediated multidrug resistance (299). Trimetrexate (70) has had extensive clinical trials and has shown activity in a number of tumors, including breast, non-small-cell lung, head-and-neck, and prostate (300), and particularly in colon cancer in conjunction with 5-fluorouracil leucovorin (301). Piritrexim (71)was chosen for development from a range of lipid-soluble diaminoheterocyclic compounds on the basis of potent DHFR...

Deregulation Of Inositol 145trisphosphate Pathway And Its Consequences

Another line of circumstantial evidence may be cited. For instance, monoterpe-nes such as limonene and perillyl alcohol have been reported not only to prevent tumour initiation and promotion, but also to inhibit tumour progression. These monoterpenes appear to inhibit the isoprenylation of G-proteins (Gould, 1997), which are a component of the signal transduction machinery (Figure 5). Similarly, abnormalities in the related pathway involving DAG and PKC may also be associated with cancers, as demonstrated by Hoelting et al. (1997) using the PKC agonist TPA (12-0-tetradecanoyl phorbol 13-acetate). They reported a 15 increase in the invasive ability of a follicular thyroid cancer cell line. In contrast, PKC inhibitors such as staurosporine, chelerythrine and calphostin C reduced invasion by 62 . CAI which inhibits calcium influx into cells, has been reported to inhibit the proliferative and invasive capacity of cell lines derived from human prostate cancer (Wasilenko et al. 1996). The...

Tumour Hyaluronan Metabolism And Angiogenesis

Cells cultured from BMRTC tissue produced low-molecular-weight HA. More recently, we have analysed the HA content size and hyaluronidase activity of allogeneic murine and rat tumours and human tumour xenografts. Although HA levels were generally increased, there was a significant reduction in HA size, compared with normal tissues, suggesting that the tumour environment may be more receptive to vascularization than HA levels alone would suggest. We also found that those tumours with low HA content or low molecular weight HA were generally metastatic, supporting the hypothesis that tumour HA metabolism may play a part in regulating tumour angiogenesis. The size of HA in this series of tumours also exhibited a loose inverse relationship to the relative levels of tumour HA and hyaluronidase activity (62,63). Similarly, Lokeshwar et al. (64) have recently reported an association between elevated hyaluronidase levels and prostate cancer progression, whilst hyaluronidase activity has been...

Protein Technologies Diagnosis and Prognosis

So far, most current diagnostic tests are based on the detection and quantification of single proteins in body fluids. The direct availability of these proteins in body fluids, in particular in the serum, is an important feature in clinical practice, because repeated sampling is possible with minimal need for invasive tests. For example, tests such as carcinoembryonary antigen (CEA) in colorectal cancer, prostate-specific antigen (PSA) in prostate cancer, alpha-fetoprotein (AFP) in hepatocellular carcinoma, etc. are currently used in clinical practice. Historically, these tests - most of them based on ELISA technology - were developed only on empirical grounds based on observation and correlation of measured levels of single proteins with the diagnosis or recurrence of disease. A common characteristic is their relatively low predictive value, so that they cannot be used alone for diagnostic purposes, and they have to be complemented with other procedures, in cancer usually a biopsy.

Calreticulin And Its Functional Diversity

The thesis that the calreticulin gene is regulated by androgen has been advocated vigorously by N. Zhu et al. (1998). This is based on the finding that androgen ablation down-regulates and its restoration up-regulates both calreticulin mRNA and protein expression in the prostate. Calreticulin is expressed at higher levels in the prostate than in the seminal vesicle and other organs and muscle. The regulation by androgen occurs only in the prostate and seminal vesicles. In vitro, the induction of calreticulin by androgen is not inhibited by inhibitors of protein synthesis, hence the suggestion that the calreticulin gene might be regulated by androgen. Furthermore, in androgen-sensitive LNCaP prostate cancer cell lines, androgen is able to block apoptosis induced by the calcium ionophore A23187. This effect of androgen can be negated by antisense calreticulin oligonucleotides (N. Zhu et al. 1999).

Impact Of Imaging Diagnostics On Cancer In Relation With Tumor Markers

In the case of lung cancer, early detection is needed to improve prognosis because most cancers are metastasized when first detected by biomarkers or by cytological assessment of sputum. Mass screening for lung cancer with low-dose X-ray spiral computerized tomography (CT) in mobile units was performed on 5483 individuals from the general population in Japan (13). The detection rate with CT was 0.48 , including cancers of less then 10 mm in diameter, whereas that of standard mass screenings done previously in the same area were 0.03-0.05 , 10 times less sensitive. This high-resolution CT also constitutes an excellent tool for confirmatory discrimination of subtypes of small peripheral lung peripheral adeno-carcinomas (71). Magnetic resonance imaging (MRI) on preoperative local staging of patients with pancreatic cancer was applied to discriminate resectability. MRI results showed 98 sensitivity, 92 specificity, and 96 accuracy in patients with suspected pancreatic tumor (72)....

Telomeres And Direct Proof Of Their

Many reports have appeared suggesting a telomere-independent mechanism of cellular senescence is present in epidermal keratinocytes (39,40) and in mammary (39), adenoid (41), thyroid (42), and prostate (43) epithelial cells. The investigators who reported these findings found that inactivation of the p16 pRB pathway (by methylation of the p16 gene or by expression of viral oncogenes such as the human papilloma virus protein E7) was required before telomerase could immortalize these epithelial cells. Many of these epithelial cells were grown in a chemically defined medium in which the proliferative life span of 10-20 doublings is much less than the approximately 50 doublings that are seen when keratinocytes are grown on feeder layers (44). We have shown that keratinocytes can be immortalized by telomerase alone without inactivating p16 when grown in the more hospitable environment provided by feeder layers (which produce additional growth factors, extracellular matrix and or epithelial...

Risk Of Second Malignancies

In an epidemiological study of HCL in Los Angeles County in 1990, it was noted that patients with a history of HCL were more than twice as likely as other cancer patients to have multiple cancer diagnoses.5 Since that time, multiple studies have confirmed that HCL patients have an increased risk for secondary malignancies. The rationale for this observation is probably dual. The primary treatment of HCL involves the use of nucleoside analogs, which lead to prolonged immunosuppression, with lower than normal numbers of CD4+ cells for more than 3.5 years.1819 This prolonged immunosuppression leads to an increase in second malignancies.19 Cheson et al. looked at patients with either chronic lymphocytic leukemia (CLL) or HCL who had undergone treatment with Nucleoside Analogs and found a total of 150 secondary cancers in 146 patients. Most of these cases were solid tumors, with a higher than expected frequency of prostate cancer.20 In a study from British Columbia, Au et al. reported that...

Osteocalcin in Cell Proliferation and Differentiation

The osteocalcin gene is expressed in consonance with the inhibition of cell proliferation and the onset of cell differentiation and ECM mineralisation (Y.P. Li et al. 1995). VD3, as discussed above, induces osteocalcin expression, but on the other hand, it inhibits cell proliferation, apparently with the mediation of cdk inhibitors. M.J. Campbell et al. (1997) synthesised a number of VD3 analogues and demonstrated that these were capable of inhibiting proliferation of the prostate cancer cell lines LNCaP, PC-3, and DU145. The inhibition of cell proliferation was accompanied by an up-regulation of the expression of the cdk inhibitors p21waf1 and p27kip1. An up-regulation of p21waf1 expression has also been encountered in VD3-induced differentiation of human MG-63 osteosarcoma cells, and this has been shown to be independent of p53 function (Matsumoto et al. 1998). Therefore, these observations seem to define a direct and novel pathway of inhibition of cell cycle progression by VD3. The...

Markers of Angiogenesis

Markers of angiogenesis have to be specific, accessible, and abundant if they are to serve as targets for therapeutic or diagnostic intervention. To date, only few good quality markers of angiogenesis located either on ECs or in the modified ECM are known. Most existing candidate markers are also expressed in some normal tissues, thus limiting their usefulness. Systematic ex vivo investigations of tumor endothelial structures using proteomic techniques 42, 43 , biopanning of phage display libraries 44-50 , or transcriptomic techniques, such as serial analysis of gene expression 51 , are revealing new candidate tumor endothelial markers. Their validation, however, requires the generation of specific monoclonal antibodies, a comprehensive immunohistochemical analysis, and quantitative biodistribution studies in animal models of angiogenesis-related diseases. Markers for angiogenesis located on the cell surface of tumor endothelial cells are the integrins av 53 52, 53 , endoglin 54 ,...

Inflammatory pathway in atherosclerosis biological basis of biomarkers in prediction and prognostication in

As data concerning the utility ofbiomarkers of inflammation in prospective cardiovascular risk prediction emerged, they appeared to fit into a pattern. One theoretical construct may help to systematize the biological basis ofbiomarkers ofinflammation in the cardiovascular arena (Fig. 4) (30). According to this hypothesis, a first wave ofprimary proinflammatory cytokines could arise from either vascular or extravascular sources (Fig. 4, top). Examples of primary proinflammatory cytokines include the soluble mediators IL-ip and tumor necrosis factor (TNF)-a. Intravascular sources could include the atheroma itself, a hotbed of inflammatory signaling, as already discussed. Extravascular sources could include foci of chronic infection, such as prostatitis, bronchitis, periodontal disease, or stasis or ischemic ulcers. Unfortunately, another potential source of extravascular inflammatory stimuli, visceral adipose tissue, will become more prominent owing to the currently increasing...

Vas deferens ductus deferens

To the ischial tuberosity then turns medially to the base of the bladder. Here it joins the more laterally placed seminal vesicle to form the ejaculatory duct which traverses the prostate to open into the prostatic urethra at the veru-montanum on either side of the utricle.

Current and Future Applications Preclinical Research Applications

Dynabeads CD3 CD28 and Dynabeads ClinExVivo CD3 CD28 have been and continue to be used extensively in preclinical studies evaluating the use of novel adoptive T cell transfer approaches for treating cancer, infectious disease, autoimmunity, and disorders associated with chemotherapy and al-logeneic transplantation. T cells have been effectively expanded from cancer patients, chronic lymphocytic leukemia CLL 38 , multiple myeloma MM 57 , non-Hodgkin's lymphoma NHL 50,58 , renal cell carcinoma RCC 59 , prostate cancer PC 60 , breast cancer BC 45 , HIV-infected patients 61,62 , and patients with autoimmune disease 63-65 .

Chemoattractant For Monocytes

The identification and cloning of MCP-1 provided an opportunity to screen tumors for their expression of a bona fide monocyte-specific chemoattractant. Table 1 lists several types of cell lines, tumor explants, and primary tumor tissues that express MCP-1. Although the list appears to be extensive, MCP-1 expression is not a universal property of tumor cells since there are many tumor types that do not express MCP-1, e.g., prostate carcinoma and many lung cancers (44).

Central Neural Mediation of Cytokine Induced Anorexia

The major hypothalamic detection site for blood-derived signals. Yet, severing the ARC from PVN or its connections with the PVN only slightly attenuated peripheral IL-1p-induced anorexia 35 , indicating that the ARC is involved but not necessary for peripheral IL-1p-induced anorexia. Several lines of evidence 20 implicate activation of hindbrain to forebrain aminergic neurons in the feeding suppression and hypermetabolic effects of circulating IL-1p. IL-1p-induced anorexia may in part be mediated through prostaglandin E2-dependent activation of serotoninergic neurons originating in the raphe nuclei and projecting to the hypothalamus 36 . In line with this idea, systemic administration of a serotonin (5-HT2c) receptor antagonist and microinjection of the 5-HT1A autoreceptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) directly into the raphe nucleus both markedly attenuated the feeding-suppressive effect of peripherally injected IL-1-p 3 . Interestingly, anorexia induced...

Physiological Role of Desacyl Ghrelin

Pressing des-acyl ghrelin showed small pheno-type, which is not attributed to poor nutritional condition. It has been found that overexpressed des-acyl ghrelin acts in the pituitary and in the hypothalamus in transgenic mice, suggesting a role of des-acyl ghrelin in the regulation of GH secretion 18 . Moreover, recent studies indicated that ghrelin and des-acyl ghrelin exhibit similar GHS-R-independent biological activities, including a cytoprotective effect on cultured cardiomy-ocytes and endothelial cells 19 , the inhibition of cell proliferation in human breast and prostate cancer lines 20, 21 , the reduction of glycerol released from rat epididymal adipocytes 22 , and the promotion of adipogenesis directly in vivo in bone marrow fat 23 . Overall, these findings suggest that the action of des-acyl ghrelin is mediated by an as-yet unknown receptor that is different from GHS-R1a.

The Role of Sex Hormones

The sex hormones exert their varied effects by promoting cell growth and cell division. As long as the cells in the target organs are healthy, with checkpoint monitors intact, there is no problem. But if a crucial gene or set of genes is defective, and the cell is being bombarded with signals to proliferate, the situation can become serious very quickly. This is the reason why cancers of the breast, uterus, ovaries, and prostate are so common and so dangerous. Cancers such as these are a natural consequence of reproductive physiology, and treatments often try to reduce the levels of sex hormones to withdraw the stimulus to the tumor cells. As discussed more fully in the next chapter, this approach is not a pleasant experience, involving as it often does the removal of the ovaries, to eliminate the synthesis of estrogen, or the testes, to block production of testosterone. The relationship between steroid hormones and cancer production introduces serious concerns regarding hormone...

Cytokine Model in Brain Responses

The simultaneous up-regulation of cytokines in peripheral organs and brain regions in response to a peripheral pathophysiological process has been reported during peripheral tumour development, peripheral cytokine administration, peripheral inflammation, and peripheral bacterial products challenge. For instance, rats bearing prostate gland adenocarcinoma cells exhibit cytokine mRNA (as an index of local production) up-regulation in the peripheral tumour, in peripheral organs such as the spleen and in discrete brain regions 31 . This cytokine up-regulation in the periphery and brain has also been observed in a non-hormone-dependent (non-adenocarcinoma) methylcholanthrene tumour model in rats 32 . In this model, intrahy-pothalamic administration of IL-1 receptor antagonist improved feeding 33 . There are also

Other Tissue Autoantibodies

Tion between neoplasia and autoimmunity results from increased incidence of both conditions in senescence. In our preliminary investigation 61 we studies 139 patients (55 of whom were aged 60 years and younger, and 84 were older than 60 years) suffering from a variety of malignant tumors for ANA, RF and antiery-throcyte antibodies (Coomb's test). There was no significant difference between the incidences of ANA and RF in the young patients and in the young controls and similarly, there was no significant difference between the incidences of ANA and RF in the elderly cancer patients and in the elderly controls. Our results suggest that the reported high incidence of ANA and RF in malignancies is a result of the old age of these patients rather than the tumor itself. However, the incidence of antierythrocyte antibodies was significantly higher in the patients than in the controls. This study was later extended to test a large battery of autoantibodies and the malignancies were grouped...

Cell Surface Adhesion Molecules

From the evidence discussed so far, it would be natural to assume that well differentiated, non-invasive and non-metastatic carcinomas will express normal or relatively high levels of cadherins, whereas tumours that are poorly differentiated and possess a high metastatic potential will not. This correlation has been shown to hold true for several tumour types including squamous cell carcinomas of the head and neck (49), lung cancer (50), prostate and bladder carcinomas (51, 52), pancreatic cancer (53) and lobular breast cancer (29). patients with head and neck squamous cell carcinoma (61), bladder cancer (51), gastric tumours (62) and prostate cancer (63, 64).

Dietary Nutritional Factors

High calorie intake has often been associated with an increased risk of prostate cancer. However, the interaction between various compounds (total fat, animal fat, saturated or un-saturated fatty acids, cholesterol, triglycerides, omega-3 fatty acids) is very complex (Wuermli 72 studies concerning intake of tomatoes and tomato-based products and blood lycopene levels in relation to the risk of various cancers. An inverse association was identified in 57 reports and 35 of them were statistically significant. The evidence for a benefit was strongest for tumors of the prostate, lung, and stomach. Conversely, no study indicated that intake of tomatoes or a high serum lycopene level led to an increased risk of cancer of any site. Numerous studies could demonstrate an inverse correlation between intake of vitamins and incidence of various types of malignant tumors. Of special interest with regard to prostate cancer were vitamins A, C, D, and E. Vitamin C is a water-soluble antioxidant in...

Is Fimbrin Involved in Cancer

The potential of fimbrin to modulate cell behaviour is obviously quite considerable. There are references in the literature since the early 1980s that fimbrin expression increases with cell transformation, especially in fibroblast cells. However, little incisive investigation seems to have been carried out. More recent investigations have pursued the worthwhile aim of establishing a role for fimbrin in neoplastic transformation and tumour progression. The expression of L-fimbrin has been investigated in cell lines derived from carcinoma of the prostate. L-fimbrin has been found in many carcinoma cell lines, but not in normal epithelial cell lines derived from the prostate. L-fimbrin occurs at higher levels in prostate cancer tissue as compared with normal prostate tissue. Immunohistochemical staining has suggested that the increase of fimbrin occurs predominantly in the glandular epithelial cells of the carcinoma, whereas in normal prostate tissue, it is found mainly in the...

Pharmacological Prevention

In the Prostate Cancer Prevention Trial (PCPT), a total of 18,882 men 55 years of age or older were randomly assigned to either receive finasteride (5 mg daily) or placebo for 7 years (Thompson et al. 2003). Digital rectal examination (DRE) was normal in all men and PSA was 3.0 ng ml or lower. During follow-up, prostatic biopsy was recommended if DRE turned abnor- mal or if the annual PSA level, adjusted for the effect of finasteride, increased above 4.0 ng ml (so-called for cause biopsy). An end-of-study biopsy was planned for all participants. Primary end point was prevalence of prostate cancer during the 7 years of study. Secondary end points included incidence of lower urinary tract symptoms (LUTS) and side effects of finasteride. Detection rate of prostate cancer was 18.4 in the finasteride group compared to 24.4 in the placebo arm, which translates into a 24.8 reduction in prevalence (p< 0.001) (Fig. 2). The relative risk reduction was consistent in all subgroups, irrespective...

The Autoimmune Response In Lung Cancer Is Similar To That In The Systemic Autoimmune Diseases

There are also indications for the development of linked antibody response in cancer. In melanoma, multiple components of the melanosome, a cellular organelle found in melanocytes, have been reported to be recognized by autoantibodies 59 . Also, we have recently identified autoantibodies to the 32- and 14-kDa subunits of replication protein A (RPA) in the sera of patients with lung, breast and prostate cancer 42 , These subunits of RPA are known to be a part of a multicomponent enzyme complex 41, 6062 involved in the metabolism of DNA 60, 63-68 , Thus, our data suggest that autoantibodies developing in cancer patients, similar to those of the systemic autoimmune diseases, may be recognized multiple epitopes of immunogenic subcellular particles. This possibility deserves further investigation.

Physical Activity Sports

The influence of physical activity on prostate cancer incidence has been looked at in two Scandinavian cohort studies. In a population-based cohort study of 53,242 men aged 19-50 years in Norway, information on physical activity was based on questionnaire responses and a brief clinical examination (Thune and Lund 1994). When occupational and recreational physical activity were combined, a reduced adjusted risk of prostate cancer was observed among men who walked during occupational hours and performed either moderate (RR, 0.61) or regular recreational training (RR, 0.45) relative to sedentary men. From a Swedish nationwide census, two cohorts of men were identified whose occupational title allowed classification of physical activity levels at work in 1960 and in 1970 (Norman et al. 2002). A third cohort included only men whose jobs required a similar level of activity in both 1960 and 1970. The incidence of prostate cancer was ascertained through record linkage to the Swedish Cancer...

Role Of Various Factors In The Development Of Cancers

When populations move from one country to another, the rates for many cancers tend toward that of the local population rather than that of their country of origin. A classic example is the incidence rates among Japanese individuals living in Osaka, Japan, in contrast to those who have moved to Hawaii (Fig. 3-9).49 Within a generation, the incidence for prostate, colon, and breast cancer begin to approach those of the United States population, whereas the incidence of stomach cancer, more prevalent in Japan, decreases. Another interesting point from the data in Figure 3-9 is that from 1970-71 to 1988-92, some of the ''more Western cancers'' became more prevalent in Japan, presumably because of a more Westernized diet and lifestyle.

Can Replicative Senescence Act To Promote Cancer

Many more studies are needed in this area. First, the variety of tissues and the range of donor ages that have been surveyed so far is very small, and it is not possible yet to determine whether the occurrence of SA-cells is an inevitable part of normal aging or alternatively evidence of a pathological process. Studies in the prostate, liver, and vascular endothelium are suggestive of an accumulation of SA-(3-gal+ cells in disease states 100-102. Second, more studies are needed to show whether SA-(3-gal+ cells are generated by telomere shortening or by some other process. The suspicion that in some cases telomere shortening is not involved exists for retinal pigmented epithelial cells, because these cells are mostly postmitotic in adult life 103. These cells may have entered the senescent state as a form of stress-induced senescence as a result of exposure to oxidative damage.

Calreticulin in Neoplasia

It would be premature to speculate on the nature of these correlative observations, but it has been suggested that calreticulin might control tumour progression by initiating a loss of apoptotic potential in tumours (Bruchovsky et al. 1996). Calreti-culin levels increased in NG 108-15 neuroblastoma glioma hybrid cells when induced to differentiate by treatment with db-cAMP (Johnson et al. 1998). Interestingly, however, antisense oligonucleotides for calreticulin do induce cell death in undifferentiated cells but not in differentiated cells. When the apoptotic pathway is experimentally induced in HL-69 cells by exposing them to geranylgeraniol, the expression of calreticulin is inhibited (Nakajo et al. 1996). Similarly, antisense calreticulin oligonucleotides seem to protect prostate cancer cell lines from calcium ionophore A23187-induced apoptosis. In this experimental system both androgen and calreticulin seem to be involved in the control of apoptotic events. A23187 induces...

Angiogenesis Blockers

Tumors, like normal tissue, cannot grow to more than a millimeter or two in diameter without being vascularized. Consequently, angiogenesis is a prime target for cancer therapy. Clinical trials are currently in progress to test angiogenesis inhibitors on cancers of the breast, prostate, brain, pancreas, lung, stomach, ovary, and cervix, as well as leukemia and lymphomas. So far the studies have had limited success. Endostatin, a widely studied drug that is toxic to endothelial cells, showed great promise in preliminary studies. It is safe to administer, but it has failed to demonstrate antitumor effects. An extract from the Asian fruit Gleditsia sinensis (GSE) has been shown to be an effective blocker ofVEGF transcription but has yet to progress beyond the basic research stage. Another compound, extracted from green tea, called GTE is known to be a powerful blocker of endothelial cell proliferation but, like GSE, it is still at the preclinical stage of development. The most successful...

Clinical Indications of Hyaluronan in Cancer

The increased accumulation of HA may thus provide an independent prognostic marker of ovarian cancer. The molecular basis for increased HA was not precisely defined but the action of growth factors and direct cellular contact with local mesenchymal cells was thought likely to have a role. Interestingly this is supported by previous studies which have shown that murine ovarian cancer cells stimulate HA production on murine mesenteric surfaces and tumour cell clumps (28). The evaluation of epithelial ovarian tumours was extended further by Hiltunen et al. (21), where HA accumulation alone, without hyaluronidase activation (the enzyme family which breaks down HA), was shown to correlate with the aggressiveness of ovarian cancer. In a prostate cancer study Posey et al. (25) evaluated the potential of HA and the Prostate cancer hyaluronidase family member, hyal-1, as prognostic markers in 70 clinical prostate cancer samples using a biotinylated HA-binding protein and anti-hyal-1 antibody....

Detection Of A Malignant Disease

From all the reports on p53 autoantibodies it seems to come up that p53 autoantibodies are in general associated with a malignant disease, whereas, healthy blood donors are rarely positive for p53 autoantibodies. Two individuals were found to express p53 autoantibodies although no tumor was detected. Both individuals were heavy smokers and diagnosed for chronic cough or a benign obstructive tracheal tumor. Both developed lung cancer within 5 or 15 months, respectively 27 . In a study of patients with prostate carcinoma, a healthy control patient was also positive for p53 autoantibodies 28 , Later, it turned out that this patient died from an undetected lung cancer. Thus, these studies might indicate that p53 autoantibodies may be early markers for malignancy and that this type of analysis allows for the detection of an unknown cancerous malignancies. However, there are also reports that p53 autoantibodies were found in patients with nontumorous diseases such as autoimmune diseases....

Cannabinoid Binding Sites

Anterior pituitary gland although not in a wide range of other rat tissues including thymus, reproductive tissues (ovary, uterus, testis, vas deferens, prostate gland), gastrointestinal tract, heart, lung, urinary bladder and adrenal gland. Results from binding assays with 3H CP 55,940 using membrane preparations obtained from tissue homogenates have confirmed the presence of specifie cannabinoid binding sites in spleen cell membranes (Kaminski et al., 1992 Rinaldi-Carmona et al., 1994) and also demonstrated the presence of such binding sites in guinea-pig small intestine and pregnant mouse uterus (Paterson and Pertwee, 1993 Das et al., 1995). Most published binding data provide no information about the types of cannabinoid receptors present in peripheral tissues as they have been obtained with receptor probes that bind equally well to CB1 and CB2 receptors or whose relative affinities for CB1 and CB2 binding sites are unknown. An exception is an investigation carried out by...

Hyaluronan and Angiogenesis

A key aspect of tumour establishment and growth involves angiogenesis. Without neovascularization, essential nutrients cannot be supplied to solid tumours, preventing their ability to proliferate, invade or metastasise. HA has been shown to have an important role in vasculature and the angiogenic process (48,82). West and Kumar (83) first showed that HA oligosaccharides increased angiogenesis and that administration of high MW HA inhibited this process (82). This may appear paradoxical to findings that show the production of high MW HA by HAS (84) is correlated to tumour progression, and that inhibition of HAS reduced prostate tumour vascularity (85). More recently, some of the key intermediates such as the tyrosine phosphorylation and membrane recruitment of PLC-g 1 were shown to be activated in bovine aortic endothelial cells by HA oligos (86). There is little doubt that the involvement of HA in the angiogenic process is complex and requires further work for clarification. However,...

HGF in tumourstromal interactions

Host stromal influence on epithelial neoplasia and malignant behavior of carcinoma cells have been noted in various types of cancers, including cancers in prostate, stomach, skin, oral cavity, mammary gland, lung, and colon (215-217). In vivo growth of certain carcinoma cells was markedly accelerated by a broad spectrum of fibroblasts, and both in vitro and in vivo invasiveness of carcinoma cells was induced by the coexistence of stromal fibroblasts (218-221). Thus host stroma-derived factor(s) is one key molecule that regulates tumour cell invasion and metastasis. In addition to stromal involvement in tumour malignancy, stromal alterations occur during malignant progression of tumours. The presence of activated fibroblasts are seen in close proximity to tumour tissues (216). Therefore, local and mutual interactions between tumour cells and stromal cells are of particular importance in regulating extracellular matrix degradation, migration, and invasion of tumour cells. Although...

Developed Countries Have the Highest Cancer Rates

Of the 14 cancers shown in the table on page 56, all but two occur with a higher incidence in developed countries (located in North America, Europe, and parts of Asia). The difference is often profound (see table on page 58). Prostate cancer, at the top of the list, is nearly six times more prevalent in developed companies than it is in undeveloped or less developed countries of the world (located in South America, Africa, and large parts of Asia). Skin cancer, specifically melanoma, is seven times more prevalent in developed countries, while the remaining cancers, shown in the table, are two to three times more prevalent in developed countries. There are two exceptions to this trend stomach cancer, which occurs with about the same incidence in developed and undeveloped countries, and liver cancer, which is more common in undeveloped countries. The equalized incidence of stomach cancer may point to the ingestion of environmental carcinogens that are present throughout the world (this...

Cancer and the North American Diet

Prostate Scientists have shown that obese women have much higher levels of estrogen (130 percent more) than do thinner women. A similar relationship is believed to influence the incidence of prostate cancer in men. In this case, the estrogen produced by the adipocytes overstimulates the cells in the prostate gland, thus increasing the risk of cancer development. The discovery of leptin and the endocrine function of fat cells provides a direct link between obesity and the high incidence of cancer in the developed world. Breast and prostate cancers are only two of the many cancers that are likely to be induced by a high-fat diet. Additional cancers, of the pancreas, liver, lung, stomach, and skin, may be attributable to both the elevated levels of sex steroids and to leptin.

Psa Ca 125 Ca 199 And

In Taiwan, a study screened a total of 41,495 asymptomatic individuals for cancer by measuring multiple tumor markers (28). The purpose of the screening was to find cancer among asymptomatic individuals. Included in the panel of tumor markers for screening were a-fetoprotein (AFP), CA 125, CA 15-3, CA 19-9, CEA, and prostate-specific antigen (PSA).

Serial Stochastic Events

The interpretation of carcinogenesis as a multistage process presents at least two non-mutually exclusive explanations for the increasing incidence of cancer with age. The first and simplest is that the tissues of an older person will have, over time, sustained the serial stochastic events involved in carcinogenesis. Accordingly, the cancers more prevalent among the aged, such as prostate, colon or breast cancer, are those involving a greater number of steps. In contrast, this hypothesis would predict that tumors more common in young people (lymphoma, leukemia, neuroblastoma, etc.) would require fewer steps in the progression from normal to the malignant state.

Peroxisome Proliferator Activated Receptors

Colon cancer in humans was shown to be associated with loss-of-function mutations in PPARy (152). Ligand activation of PPARy in cultured breast cancer cells causes extensive lipid accumulation, changes in breast epithelial gene expression associated with a more differentiated, less malignant state, and a reduction in growth rate and clonogenic capacity of the cells (150). These data suggest that the PPARy transcription system can induce terminal differentiation of malignant breast epithelial cells and thus may provide a novel therapy for human breast cancer. Human prostate cancer cells were found to express PPARy at prominent levels while normal prostate tissues demonstrated a very low expression (143). It has recently been shown that PPARy is expressed in human prostate adenocarcinomas and cell lines derived from these tumors. Activation of this receptor with specific ligands, such as troglitazone, exerts an inhibitory effect on the growth of prostate cancer cell...

Causes Of Hyponatremia

Posttransurethral resection of prostate bladder tumor resection of the prostate is a common cause of hyponatremia because of the large volume of mannitol-containing bladder irrigation fluid used intraopera-tively. For either of these states, correction of the glucose level (or excretion of the mannitol) corrects the hyponatremia.

Central Dogma Of Tumor Progression

Actually be the same genes involved in a selective growth advantage for these cells. These cells maybe lurking even in early-stage cancers. That is, some cancers are predestined almost from the beginning to evolve into invasive, metastatic tumors and some are not. This possibility has huge implications for cancer screening, diagnosis, and choice of therapy. Numerous women receive a diagnosis of ductal carcinoma in situ of the breast based on mammography screening, and many men receive a diagnosis of prostate cancer based on a prostate-specific antigen (PSA) test and subsequent biopsy. And yet many of these patients have indolent tumors that would not affect their overall life expectancy, and they still often undergo significant surgical and drug treatments. The problem is that we are only beginning to be able to tell (e.g., by gene expression arrays) which of these so-called early-stage cancers will be lethal and which ones won't.

The Great Cancer Myths

In most polls, it is the most feared disease of all. Coupled with this are the almost daily media reports of another carcinogen or cancer risk being found in our environment that produce a setting for the sometimes hysterical fear that cancer lurks around every corner. Epidemiological pronouncements that one out of eight women will die of breast cancer or one of every four men will get prostate cancer, while perhaps having some statistical validity if everyone would reach age 80 and die of nothing else, belies the real risk of getting and dying of cancer. A study published by Wo-loshin et al.151 puts this rate in a more rational context. never smoked, 14 of 1000 will die of heart disease, 5 of lung cancer, and 7 of breast cancer by the time they reach 70 years of age. For 60-year-old men who are smokers, 84 of 1000 will die of heart disease and 98 of lung cancer, but only 4 of 1000 will die of prostate cancer.

Immunotherapy Approaches

MICA was the first NK receptor ligand that was found to be shed during tumor development. MICA is commonly expressed on multiple tumor types of epithelial origin, including gastrointestinal, lung, breast, kidney, ovary, prostate, colon, and hemato-poietic malignancies. The mechanism of MICA shedding is dependent on metallo-proteinases (Salih et al, 2002). Use of a matrix metalloproteinase inhibitor (MMPI) prevented MICA shedding and led to the accumulation of ligands on the cell surface, while a serine protease inhibitor had no effect.

ZO1 and the MAGUK protein family

Paracellin-1 has a structure identical to occludin, i.e. four membrane spanning regions forming two extracellular loops (figure 3). It appears that paracellin-1 is uniquely expressed in kidney tissues, as no mRNA has been detected in other tissues, including thymus, testis, prostate, ovary, small and large bowels, and peripheral leukocytes.

Clinical features

1 Prostatectomy for benign prostatic hypertrophy involves removal of the hypertrophic mass of glandular tissue from the surrounding normal prostate, which is compressed as a thin rim around it a false capsule (Fig. 88). This is usually performed transurethrally by means of an operating cystoscope armed with a cutting diathermy loop. During this procedure, the verumontanum, (colliculus seminalis), is an important landmark. The surgeon keeps his resection above this structure in order not to damage the urethral sphincter. If the prostate is very enlarged, open prostatectomy is indicated. The gland is approached retropubically, the capsule incised transversely and the hypertophied mass of gland enucleated. Anterior to the urethra the prostate consists of a narrow fibromuscular isthmus containing little, if any, glandular tissue. Benign glandular hypertrophy of the prostate, therefore, never affects this part of the organ. 3 The fascia of Denonvilliers is important surgically in excising...

Reflectance Measurement of Carotenoids in Skin

300 Chroma Meter

The larger number of conjugated carbon bonds in lycopene compared to the other carotenoids in skin produces an absorption band shift that can be used to measure lycopene independently of the other carotenoids (88). It is possible in this way to assess this carotenoid independently from the other dietary carotenoids. There is considerable interest in a specific role for lycopene in prevention of prostate cancer and other diseases (83,91), and a noninvasive biomarker for lycopene consumption would be of tremendous utility.

Age And Natural History Of Cancer

Beneficial to older post-menopausal women 45. Likewise, age does not seem to reduce the benefits of adjuvant chemotherapy in patients with stage III cancer of the large bowel46. The only situations in which the natural history of cancer may suggest to forgo the use of antineoplastic treatment include smoldering AML and early stage prostate cancer in man aged 70 and older. Though smoldering acute leukemia is an obsolete term, this definition may still be helpful to encompass two conditions hypoplastic acute leukemia, that is AML with a marrow cellularity lower than 10 and AML associated with Myelodysplasia, with a percentage of blasts in the bone marrow between 20 and 30 , that does not undergo any significant change over three months. In both cases the predominant clinical picture is pancytopenia, the incidence of leukostasis is negligible, cytotoxic chemotherapy is associated with low therapeutic response and high risk of early mortality, while supportive treatment with transfusion...

Suppression of Autoimmune Disease by Regulatory Cells from Donors with or Without the Relevant SelfAg

In view of differential suppression of autoimmune prostatitis (AIP) and autoimmune thyroiditis by T cells from Ag-positive vs Ag-negative cell donors (described below), how do we explain their equal suppression of AOD Our interpretation is that even if the regulatory capacities of male and female CD4+CD25+ T cells for AOD suppression are different, they are equalized when the cells encounter the endogenous ovarian Ag in the young d3tx host. Indeed, we have shown that ovarian Ags (mater and ZP3) are expressed from birth and have the capacity to stimulate T cells on day 3 (Alard et al. 2001). This is also exemplified by the process of diversified autoAb response that depends on de novo B cell response to endogenous ovarian Ag. Immunized female mice with a ZP3 peptide that contains T but not native B epitope (in CFA) elicited Ab response to a distant native ZP3 B cell epitope within 7 days, 2 days after detectable response to the ZP3 T cell epitope (Lou et al. 1996). Other examples of...

Discussion 31 Validity of Data

Between 2001 and 2003 the completeness and accuracy of our data on co-morbidity in the Eindhoven Cancer registry were validated in a random sample of 2607 patients with colorectal, lung, breast and prostate cancer and non-Hodgkin's lymphoma aged 40 and older and diagnosed between 1995 and 1999. Co-morbidity scored by the registry team was compared with that scored by a team of a surgeon and an epidemiologist. Recording of co-morbidity proved to be entirely correct for almost 70 (ranging from 59 to 72 ) of patients. Some under-registration occurred especially of cardiovascular conditions (Internal report, 2002). This appeared to be mainly due to the use of unknown terminology, unknown abbreviations or illegible handwriting of the specialist. Although the unregistered conditions were at the time not very severe, this would imply that the real effects of co-morbidity on treatment and survival are probably stronger than those presented in this chapter and in our publications.

Dna And Protein Array Antibody Array

Using a high-throughput proteomic classification system, Adam et al. (65) provided an accurate and innovative approach for the early detection diagnosis of prostate cancer. A protein biochip surface enhanced laser desorption ionization mass spectrometry approach coupled with an artificial intelligence learning algorithm was used to generate protein profiling with proteomic patterns that differentiate prostate cancer from noncancer cohorts. Feroze-Merzoug et al. (66) also has measured the gene expression patterns (both mRNA and protein expression profiling) to differentiate between normal prostate and prostate tumor, and between tumors at different stages.

The Role Of Thymosin Family Actinbinding Proteins In Actin Dynamics

There are also important implications of thymosin overexpression for cell migration in the context of cancer invasion, because thymosins have been reported to be overexpressed in neoplastic cells (see below). Especially significant are the reported specificity of response by endothelial cells to Tp4 and the associated overexpression of metalloproteinases. Metalloproteinases have been closely associated with breaching of the endothelium and aiding the diapedesis of cancer cells into the vascular compartment (Sherbet and Lakshmi, 1997b). Tp4 is reported to be highly expressed in the intrinsically highly motile embryonic mesenchymal cells (Carpintero et al. 1996). The expression of Tp15 seems to be up-regulated in the highly motile Dunning rat prostate cancer cell lines. Besides, the transfection of antisense constructs of Tp15 gene apparently alters the motility of these cells (Bao et al. 1996). As stated before, the putative association of overexpression of TP4 with increased...

Antitumor Sulfonamides

The development of CAIs possessing potent tumor cell growth inhibitory properties was reported by this group (Supuran and Scozzafava 2000b, 2000c Scozzafava and Supuran 2000a Supuran et al. 2001). Such compounds were discovered in a large screening program in collaboration with the National Institutes of Health (NIH) of sulfonamide CAIs. Several hundred aromatic heterocyclic sulfonamides were assessed in vitro as potential inhibitors of growth of a multitude of tumor cell lines, such as leukemia, nonsmall cell lung cancer, ovarian, melanoma, colon, CNS, renal, prostate and breast cancers. The active compounds (most of them nanomolar inhibitors of CA II and CA IV), of types 4.212 to 4.223, belong to both the aromatic and the heterocyclic sulfonamide classes and showed GI50 values (molarity of inhibitor producing a 50 inhibition of tumor cell growth after a 48-h exposure to the drug) in the micromolar range (Supuran and Scozzafava 2000b, 2000c). Better antitumor compounds were then...

Historical Perspectives

Cancer cells react to hypoxic conditions by up-regulating expression of HIF-1, which is a transcription factor that in turn up-regulates expression of genes involved in glycolysis, glucose transport (GLUT-1), angiogenesis (VEGF), cell survival, and erythropoiesis. HIF-1 expression has been observed in cancers of the brain, breast, colon, lung, ovary, and prostate and their metastases but not in the corresponding normal tissues. Its expression in tumors correlates with poor prognosis.

Genital and Urinary Tracts and Mesothelial Cells as Hyaluronan Producers

The expression of hyaluronan in the simple epithelia of the male reproductive tract and its accessory glands is more active than that in the gut and intestine. Distal epididymis, vas deferens, seminal vesicle, prostate, and Cowper's gland show hyaluronan located mainly on the lower basolateral surface, but with little on the apical surface (Fig. 2c-f) (38). In these epithelia, the location of CD44 correlates with that of hyaluronan on the basolateral surfaces. This distribution suggests that hyaluronan is mostly synthesized and remains bound on the basal side of the adjacent epithelial cells. However, the lumen of the seminal vesicle, prostate and Cowper's gland (Fig. 2c-e) contain hyaluronan, suggesting that it is either secreted from the apical surface, or passes the cell junctions in the lateral sides of the cells. There is an extensive pool of hyaluronan in the underlying stroma of these glands, a potential source of the epithelial and lumenal hyaluronan. Interestingly, testis...

Hyaluronan in the Stroma of Epithelial Malignancies

The connective tissue stroma that surrounds most epithelial cancers is enriched in hyaluronan. Examples of tumors with a hyaluronan 'halo' include breast (27), prostate (53), ovarian (54), lung (33), gastric (29), colon (36), thyroid (55), and skin squamous cell (56) carcinomas. These hyaluronan deposits can serve as strong indicators of unfavorable prognosis for the patients (27,33,53-55,57) and probably contribute to the spreading of the malignant epithelial cells. Several mechanisms are likely to contribute to the hyaluronan accumulation. The malignant epithelial cells secrete (growth) factors, like TGFb (58), that stimulate the synthesis of hyaluronan by the stromal cells in a paracrine manner (59,60).

Imbalance Between Regulatory T Cells And Conventional T Cells

(Francois Bach, 2003 Shevach, 2002 Von Herrath and Harrison, 2003 Wood and Sakaguchi, 2003). In homeostatic conditions in the human and mouse, CD4+CD25 + Treg cells are found primarily in thymus, peripheral blood, lymph nodes, and spleen (Sakaguchi, 2005 Shevach, 2002). Under these conditions, it appears that Treg cells exhibit an equal distribution among the different lymphoid compartments. Notably, more than 25 of CD4+ T cells are phenotypically and functionally Treg cells in normal bone marrow (Zou et al, 2004). The chapter authors' unpublished data further show that the prevalence of Treg cells reach up to 50 in the bone marrow in patients with prostate cancer. The data suggest that in a homeostatic situation, there exists an imbalance between Treg cells and conventional T cells in the bone marrow, and this imbalance is further enforced in cancer patients. In summary, Treg cells accumulate to high levels in the bone marrow, and their prevalence appears to be substantially elevated...

Racial Difference In Mm Incidence

While many cancers (namely, those of the esophagus, cervix, stomach, pancreas, larynx, and prostate) have a higher rate among blacks than whites, within the hematopoietic system, MM is the only malignancy with a higher incidence among blacks. Asians have the lowest incidence rate of MM (less than

Summary and Conclusions

Cell shape changes, and provide a suitable environment and signals that facilitate re-epithelialization during wound healing. In contrast, many simple non-stratified epithelia are completely negative in hyaluronan staining or express a limited signal on the basolateral surface. However, injury or dispersal of these cells, for example those in the intestinal and renal tubular epithelia, upregulates the expression of CD44 and Has2, and hyaluronan staining appears on the injured cells. Malignant transformation can also turn on hyaluronan synthesis in epithelia normally devoid of detectable hyaluronan and promote cancer progression by enhancing cell proliferation, migration, survival from apoptosis, and possibly through enhanced tumor angiogenesis. Hyaluronan from or through the epithelium of prostate and other male accessory sex glands accompanies ejaculated spermatozoa, which are also greeted by hyaluronan in the fallopian tubes. Hyaluronan provided by these epithelia may have a...

Cannabinoid Receptor Agonists with Selectivity for CBX or CB2 Receptors

Cb1 Cb2 Receptors

Although by far the highest concentrations of CB1 and CB1(a) mRNA are to be found in the CNS (Galiegue et al., 1995 Shire et al., 1995), it has been possible, largely by the application of reverse transcription coupled to the polymerase chain reaction, to demonstrate the presence of both these mRNAs in many peripheral tissues. Outside the CNS, the highest levels of human CB1 mRNA are in pituitary gland and immune cells, particularly B-cells and natural killer cells (Galiegue et al., 1995). As detailed by Pertwee (1997), other peripheral tissues of human, dog, rat and or mouse that contain CB1 mRNA include immune tissues (tonsils, spleen, thymus, bone marrow), reproductive tissues (ovary, uterus, testis, vas deferens, prostate gland), gastrointestinal tissues (stomach, colon, bile duct), superior cervical ganglion, heart, lung, urinary bladder and adrenal gland. CB1(a) mRNA is thought to exist as a minor transcript, the ratio of CB1(a) to CB1 mRNA in humans never exceeding 0.2 and, in...

Expression Pattern in Mammals

The expression level of the mammalian ACBP is slightly affected by feeding status. Fasting rats for 24 hours resulted in a 33 decrease in liver ACBP levels 30 and in reduced ACBP mRNA level as well 31 , whereas the level in heart and kidney was unaffected. High-fat diet for 48 hours increased liver ACBP levels by 36 . Hepatic levels of ACBP continued to increase and remained elevated with prolonged exposure to high fat (28 days). Heart ACBP did not respond to short-term fat feeding but was increased after prolonged exposure 30 . Androgens, which stimulate growth of the human prostate cancer cell line LNCaP 32 , also stimulate de novo fatty acid synthesis, cholesterol synthesis, and lipid accumulation and induce ACBP expression in this cell line 33 . Similarly, androgens induce ACBP expression in several accessory sex organs in the male rat 34 . ACBP expression is also significantly induced during in vitro differentiation of 3T3-L1 pre-adipocytes 35 , a process that is accompanied by a...

Osteotropism Of Metastatic Dissemination

So far as prostate cancer is concerned, ICTP has been reported to reflect bone metastasis more accurately than other markers, including PSA (prostate-specific antigen). Osteocalcin showed no correlation with metastatic spread (Maeda et al. 1997). In another study, PICP and BA-1p were found to increase with progression as indicated by bone scans. A slight increase in osteocalcin was also reported in patients with remission of metastatic bone lesions, but not related to progression (Koizumi et al. 1995). Obviously more clinical trials are needed to arrive at any firm conclusions. This need is underlined by laboratory work on the differentiation of osteoblastic cells, using conditioned media of the human prostatic carcinoma PC-3 cells and cell extracts. The effects of the conditioned medium have been studied on two osteoblastic cell lines, namely, a primary cell line derived from foetal rat calvaria and a rat osteosarcoma cell line ROS 17 2.8. The conditioned medium inhibited bone nodule...

COX2 Selective Inhibitors Celecoxib Rofecoxib and Valdecoxib

COX-2 is a bifunctional enzyme possessing both cyclo-oxygenase and peroxidase activities. Selective COX-2 inhibitors inhibit PG biosynthesis (anti-COX-2 activity) but do not, or only partially, affect the peroxidase activity of COX, which can generate proximate carcinogens. In experimental animals, selective inhibitors of COX-2 such as cele-coxib reduce the formation of head and neck, col-orectal, stomach, lung, breast and prostate tumours. In addition to preventing tumorigenesis, selective COX-2 inhibitors suppress the growth of established tumours. A selective COX-2 inhibitor was also observed to decrease the number and size of metastases. In most studies, selective COX-2 inhibitors decrease the rate of tumour growth rather than cause a reduction in tumour size 124-126 . Therefore, significant preclinical evidence strongly supports the potential role for these inhibitors for the treatment of cancer.

The Relationship Between Sun Exposure and Other Diseases

There is in Australia unanimous agreement by the ACOD, OA, ANZBMS, and CCA that there is high-level evidence for the harmful effects of sun exposure in terms of skin cancer and for the beneficial effects of sun exposure in maintaining adequate vitamin D levels to protect against bone fracture (Trivedi et al. 2003). However, all parties agree that substantially more evidence is required before conclusions can be drawn between sun exposure and a possible beneficial effect with other cancers such as breast, prostate, bowel, or non-Hodgkin lymphoma and autoimmune diseases such as multiple sclerosis. The biological pathways underlying these empirically observed observations are still not clear and in some instances the epidemiological evidence is equivocal. It was agreed by all parties that it is not appropriate to make statements about a protective effect of UV radiation exposure for these diseases because substantially more studies with good individual exposure measures by season is...

Osteonectin Expression In Cancer Development And Progression

Osteonectin reportedly occurs in a wide spectrum of cancerous tissues from human subjects. Porter et al. (1995) found high osteonectin immunoreactivity in invasive tumours of the GI tract, breast, lung, kidney, ovary, brain, and adrenal cortex. They state that normal tissues show low levels of reactivity. It is somewhat paradoxical that trophoblast cells, which are a highly invasive cell component of the placenta, show low levels of reactivity. Nevertheless, bone extracts and osteonectin itself have been found to enhance the motility in vitro of prostate epithelial cells as well as prostate cancer cells (Jacob et al. 1999). The presence of osteonectin has also been demonstrated in normal as well as adenoma of human thyroid (Burgi-Saville et al. 1997). However, there is a reasonable body of evidence that suggests a close association of osteonectin expression with the progression of human melanomas. Osteonectin is not expressed by normal melanocytes and it is weakly expressed in a small...

Identification Distribution And Regulation Of Ca

Tureci et al. (1998) and Ivanov et al. (1998) have also shown that CA12 mRNA is expressed in adult kidney, pancreas, colon, prostate, ovary, testis, lung and brain (Figure 9.1). The CA XII protein was found in normal endometrium (Karhumaa et al. 2000), colon (Kivela et al. 2000) and kidney (Parkkila et al. 2000a), suggesting an important physiological role for this enzyme in ion transport and fluid concentration. In the comparative immunohistochemical study, expression of CA XII and CA IX in normal adult tissues was detected in highly specialized cells and for most tissues did not overlap (Ivanov et al. 2001).

Osteonectin Homologues And Their Putative Tumour Suppressor Properties

Hevin is expressed ubiquitously in most normal tissues and in diseased tissues of nonneoplastic origin. There may be differences in the patterns of their distribution in normal tissues, as demonstrated for SC1 (Soderling et al. 1997). The expression of hevin has been reported to be down-regulated in many neoplasms, e.g., in non-small cell lung carcinome (NSCLC) (Bendik et al. 1998) and adenocarcinoma of the prostate (P.S. Nelson et al. 1998). Claeskens et al. (2000) transfected hevin cDNA into HeLa-35 cells, which do not express indigenous hevin. The transfected hevin cDNA negatively regulated proliferation and seemed to block Gj-S transition of cells. Therefore, Claeskens et al. (2000) suggest that hevin may be a putative suppressor gene. However, it might be premature to label a gene as a suppressor gene merely on the basis of possible inhibition of cell proliferation. It ought to be stated, in defence of the postulate, that hevin does possess anti-adhesion properties, can inhibit...

Species Differences in Selective Accumulation of Carotenoids Animal Models

Ferrets, a species known to absorb carotenoids, can accumulate lycopene in tissues, with liver > intestine > stomach prostate (and not detectable in testes) (24,25). Rats fed lycopene at the same amount per kg body weight accumulated greater concentrations of lycopene in tissues than do ferrets, but with the same order of relative concentration (25). In contrast, rats normally do not have detectable -carotene in liver when fed at the same concentrations at which ferrets do accumulate -carotene in liver (25). Lack of accumulation of -carotene in rat is perhaps due to greater -carotene cleavage activity in the rat.

Genomic Signature Induced by hCG and Pregnancy

Ing by 42 days postpartum post-hCG treatment. Among these genes were the fatty acid binding protein, the EST Rn.37635 with high homology to BCL7B gene, cathecol-O-methyltransferase, and the EST genes Rn. 5953, Rn.22912, and Rn.4339 (Mailo et al. 2002). The upregulation of cathecol-O-methyltransferase is significant because it can be involved in the conjugation of estradiol and cathecol estrogens, reducing the carcinogenic effect of these hormones. Genes related to the apoptotic pathways, such as testosterone repressed prostate message 2 (TRPM2), interleukin 1 -converting enzyme (ICE), bcl2, bcl-XL, bcl-XS, p53, p21, and c-myc were also upregulated from three to fivefold (Mailo et al. 2002) (Fig. 7). We have shown that the activation of programmed cell death genes occurred through a p53-dependent process, modulated by c-myc and with partial dependence on the bcl2-family related genes (Srivastava et al. 1998, 1999 J. Russo and I.H. Russo 2000). In this cluster were also included...

The Fimbrin Family Of Actinbinding Proteins

Another membrane organelle with which fimbrin might be associated in organising a signal transduction machinery is the caveola. Caveolae are plasma membrane invaginations, of 50 to 100 nm dimension, that occur in many cell types. Caveolae have been attributed with many functions, notably transport of molecules across endothelia and signal transduction (Lisanti et al. 1995). A major component of caveolae is a 21- to 24-kDa protein called caveolin. Caveolin is said to function as a scaffolding protein that organises the signalling molecules in the caveolae. That caveolae contain essential components of the signal transduction machinery may be deemed to be firmly established. Thus caveolin has been shown to interact directly with signal transduction molecules such G-protein a subunits and the ras protein (Lisanti et al. 1995 Song et al. 1996). The receptors for PDGF and EGF are located in caveolin-rich microdomains, and caveolin has been shown to interact directly with the EGF receptor...

Hormonal Influence On Cancer

In 19418 it was shown that prostatic cancer with metastases was made worse by androgen and made better by oestrogen (stilboestrol). Activity of this cancer is particularly readily observable since the plasma prostate-specific antigen (PSA) concentration provides a reliable marker. Indeed the availability of some means of reliably measuring effect is crucial to the use of drugs in cancer.

Proteinases And Their Inhibitor 61 MMP2 and

Elevated MMP-2 and MMP-9 have been found in many human cancers such as breast, colon, prostate, and ovarian and have been associated with increased metastatic potential. They may be secreted by tumor cell themselves or secreted by host cells within the tumor stroma (25).

D CD44Hyaluronan Interactions in Tumor Invasion and Metastasis

There is long standing evidence that many solid tumors are enriched in hyaluronan (163). As far back as the beginning of the 20th century there was the description of a 'mucinous substance' associated with malignant breast carcinoma, analogous in nature to that found in umbilical cord (164). Higher levels of hyaluronan are associated with poor prognoses in many cancers including human ovarian, breast and prostate carcinomas (165-168). Coincident with this is the finding that CD44 is often upregulated in several of the same tumor tissues (36,169,170). Given the close association of extracellular matrix receptors participating in adhesion and migration, a predicted facilitatory role for CD44 during invasion and metastasis is well warranted. A necessary question is whether binding to hyaluronan is a necessary component of CD44's positive function in invasion and or metastasis. Bartolazzi et al. (171) demonstrated that stable transfectants of CD44H in human melanoma cell line MC acquired...

Calpains In Cell Proliferation And Apoptosis

Calpains often have been attributed with the ability to induce apoptotic cell death (Figure 21). They are said to be actively associated with T-cell activation and apoptosis (Squier et al. 1994 Sarin et al. 1995 S.J. Martin and Green, 1995). In mature T lymphocytes the induction of apoptosis by TCR is protease dependent (Sarin et al. 1995). The binding of the appropriate ligand of the TNF family to the Fas receptor initiates the activation of caspases and the down-stream protease cascade that leads ultimately to DNA degradation (see below). Dexamethasone is known to induce apoptosis of thymocytes, accompanied by Ca2+-dependent proteolytic activity. This is also accompanied by the autoproteolysis of the capn1 proenzyme, which suggests that calpain activation is taking place. Calpain inhibitors block apoptotic death (Squier et al. 1994). However, inhibitors of calpains have also been found to induce apoptosis. W. Zhu et al. (1995) found that two calpain inhibitors caused apoptosis of...

Statistics for Assessing Expression

Table 8.2 Comparative EST Counts for Five Genes Sequenced from Normal Prostate, Stage B2 Cancer, Stage C Cancer, and Benign Prostatic Hyperplasia (BPH) cDNA Libraries Prostate - All Other Table 8.2 Comparative EST Counts for Five Genes Sequenced from Normal Prostate, Stage B2 Cancer, Stage C Cancer, and Benign Prostatic Hyperplasia (BPH) cDNA Libraries Prostate - All Other

Human Diseases Linked to Inherited Defects in DNA Repair Genes

A number of abnormalities in nucleotide excision repair including the syndromes xeroderma pigmentosum, Cockayne syndrome, and tri-chothiodystrophy are associated with abnormalities of organ function and maintenance, skin disorders, sun and radiation hypersensitivity, malignant transformation, and, to a lesser extent, premature aging with the loss of hematopoietic function and bone structure. These syndromes are also associated with premature cancers, both skin and epithelial cancers such as prostate cancer and lung cancer, and leukemias (de Boer

Expression of Hyaluronan and Hyaluronidase in Cancer Cells of Epithelial Origin

Recent experimental research has brought extensive evidence supporting the idea that 'Has' expression and hyaluronan synthesis in tumor cells promote malignant growth (61). Transfected Has3 gene enhances the malignancy of prostate cancer cells (64). Overrepresentation of the chromosomal region 8q23-24 is common in prostate cancer and forms an unfavorable prognostic factor. This region contains Has2, which is overexpressed in an aggressive prostate cancer cell line (65). Accordingly, prostate cancer cells with high Has2 expression have a higher affinity to bone endothelial cells, and form more metastases (66), while antisense inhibition of Has2 or Has3 reduces metastasis and subcutaneous growth of implanted prostate cancer cells (67). Mouse mammary carcinoma cells with a transfected overexpressed Hasl gene showed higher metastatic activity than their parental cells, while an inactivating mutation in HAS1 reduces metastasis (68). Metastasis is also increased by cell surface hyaluronan...

Pharmacokinetic Properties

The pharmacological properties of the par-enteral penicillins and cephalosporins are summarized in Table 14.5 (147-149). In general, j3-lactam antibiotics penetrate most areas of the body except the eye, prostate (except aztreonam), and uninflamed meninges. Although entry into the cerebrospinal fluid (CSF) is satisfactory with most of the penicillins and carbapenems, only certain cephalo-sporins reach therapeutic levels in the CSF. Protein binding varies from 2 to 98 . The serum half-life of penicillins is short, ranging from 0.5 to 1.5 h. The half-life of cephalospo-rins, and especially the third-generation ceph-alosporins, tends to be longer. The half-life of ceftriaxone, the longest of all these agents, is 8 h. Most penicillins, cephalosporins, and aztreonam are removed intact by renal excretion, and those require dose modification in patients with renal impairment. However, the isoxazolyl penicillins (nafcillin and oxacillin), the ureidopenicillins, and a few cephalospo-rins...