■ Mild myelosuppression (onset 7-10 days24)

■ Hepatotoxicity, jaundice (onset typically 2-3 months24)

6-Thioguanine, 6-TG

Guanine analog; incorporated into DNA resulting in chain termination25


■ DLT = Myelo-suppression (onset 7-10 days26)

■ Mild nausea/vomiting

■ Immunosuppression26

Pyrimidine analogs Cytarabine, Cytosine arabinoside, Ara-C, Cytosar-U

Cytidine analog; incorporated into DNA resulting in chain termination; also inhibits DNA polymerase resulting in decreased DNA synthesis/repair

AML, ALL, CNS Moderate dose leukemia, NHL ■ DLT = Myelo-suppression

(onset 4-7 days27)

■ Cerebellar toxicity (onset typically 5 days28)

■ Myelosuppression

■ Severe nausea/vomiting (onset 1-3 h, typically lasts 3-8 h27)

■ Conjunctivitis

■ Transient hepatic dysfunction (elevation of serum transaminases)

■ Pulmonary complications

■ "Ara-C syndrome": allergic reaction characterized by fever, myalgias, rash, conjunctivitis (onset 12 h after infusion28)

Table 101.2 continued


Mechanism of action

Clinical uses

Common toxicities

Gemcitabine, Gemzar

Cytidine analog; incorporated into DNA resulting in chain termination;29,30 Also inhibits ribonucleotide reductase, depleting cells of deoxyribonucleotides required for DNA synthesis

Investigational use in Hodgkin's disease, cutaneous T-cell lymphoma, mantle cell lymphoma, CLL

■ DLT = Myelo-suppression (onset 7-10 days31)

■ Hepatic transaminase elevations (transient)

■ Proteinuria, hematuria

■ Generalized rash

■ Flu-like symptoms, fever (onset 6-12 hours31)

Decitabine, 2'-deoxy-5-azacytidine, Aza dC, DAC, dezocitidine

Cytidine analog; incorporated into DNA resulting in chain termination; once incorporated into DNA, inhibits DNA methyltrans-ferase enzymes (DNMTs), preventing the transfer of a methyl group to DNA strands32. Formerly silenced genes are subsequently activated, altering cell differentiation and apoptosis pathways.

Investigational studies in refractory AML, CLL, Small lymphocytic lymphoma, MDS

■ Myelosuppression (onset 14 days, may last up to 30 days)

■ Nausea/vomiting

■ Fatigue, lethargy

■ Hepatic transaminase elevations


Cytidine analog; incorporated into DNA resulting in chain termination; once incorporated into DNA, inhibits DNA methyltransferase enzymes (DNMTs), preventing the transfer of a methyl group to DNA strands32. Formerly silenced genes are subsequently activated, altering cell differentiation and apoptosis pathways. Also incorporated into RNA, altering tRNA methylation and inhibiting protein synthesis32.

CML, AML, myelodysplasia

■ Myelosuppression

■ Nausea/vomiting

■ Mutagenic potential




Inhibits adenosine deaminase, which metabolizes adenosine and deoxyadeno-sine; leads to accumulation of deoxyadenosine triphosphate (dATP), which inhibits ribonucleotide reductase and causes cell death

Hairy cell leukemia

■ DLT = Myelo-suppression (onset 7-10 days33)

■ Immunosuppression

■ Severe nausea/vomiting (onset 12-24 h after infusion11)

■ Transient hepatic transaminase elevations

■ Nephrotoxicity and neurotoxicity (rare at current doses)

■ Transient lethargy, confusion

Folic acid analog Methotrexate

Folic acid analog; binds DHFR and inhibits conversion of folic acid to active "tetrahydro" form, which deprives cells of necessary precursor for thymidylate and purine synthesis9

ALL, CNS leukemia, NHL, BMT

■ Mucositis, stomatitis (onset 3-7 days11)

■ Hepatic transaminase elevations (onset 12-24 h, usually lasts 10 days11)

■ Pulmonary toxicity

■ Nephrotoxicity

°DLT= dose-limiting toxicity.

°DLT= dose-limiting toxicity.

Antimetabolites: Selected nucleoside analogs Cytarabine Cytarabine is an antimetabolite that is currently considered the foundation of treatment for AML. It is one of the most active agents available against this disease and has been considered an integral component of induction and postremission therapy for the past two decades. In addition, cytarabine exhibits significant activity against lymphomas, meningeal leukemia, and meningeal lymphoma. It has little use in the treatment of solid tumors. Cytarabine is administered in a wide range of doses, and evidence supports a significant dose-response effect.34

Chemically, cytarabine is the arabinose analog of the nucleotide base cytosine. Arabinose analogs differ from human analogs by the placement of a hydroxyl group on the sugar moiety of the nucleoside. Cytarabine penetrates cells via a carrier-mediated transport process, where it must be phosphorylated by the enzyme deoxycytidine kinase (dCK) to its active form, ara-CTP. Because of its structural similarity to cytosine, ara-CTP is directly incorporated into DNA in place of cytosine, where it terminates strand elongation by inhibiting DNA replication. This antimetabolite effect is thought to be the main mechanism of cytarabine activity at moderate doses (100-200 mg/m2). In addition, cytarabine further affects DNA synthesis by direct inhibition of the enzyme DNA polymerase, which is responsible for strand elongation as well as DNA repair. The degree of activity correlates linearly with the degree of incorporation into DNA. This is heavily influenced by the plasma cytarabine concentration.35

Pharmacokinetics/metabolism: Cytarabine is degraded within the cell by cytidine deaminase to the inactive compound uracil arabinoside, or ara-U. Cytarabine is widely distributed in the body, with a volume of distribution approximating total plasma volume. It penetrates the CNS and achieves concentrations approximately 20-40% of simultaneous plasma levels.19 Cytarabine is metabolized extensively in the liver and excreted as metabolites within 36 h; approximately 80% is excreted in the urine as ara-U. The plasma halflife is 2-6 h, while the CSF half-life is longer, ranging from 2 toll h.519

Toxicity: Toxicity of cytarabine is dose-dependent; at higher doses (>1 g/m2), cytarabine is dose-limited by cerebellar toxicity. This often manifests as a syndrome of dysarthria, nystagmus, and ataxia, and may progress to generalized encephalopathy and seizures. Some degree of CNS toxicity has been documented in up to 40% of patients receiving high-dose cytarabine.19 This is typically reversible upon discontinuation of drug, but may be permanent. It is highly correlated with older age, renal dysfunction, and elevated alkaline phosphatase levels, and dose adjustments are strongly recommended for both groups of patients.519'3637 In addition, high-dose cytarabine can cause severe conjunctivitis, maculopapular skin rash, palmar-plantar erythema, and hepatic toxicity characterized by cholestatic jaundice. At lower doses, cytarabine can cause significant myelosuppression. Alopecia and dose-related nausea and vomiting are common as well.5

Gemcitabine Gemcitabine is a pyrimidine analog, structurally similar to cyarabine, and was initially developed as an attempt to expand upon the cytotoxic effects of the latter agent. Chemically, it differs from cytarabine by the substitution of geminal fluorines for the hydroxyl group at the 2' position.20 38 This chemical alteration allows for greater cellular permeability and increased affinity for the enzyme dCK, which phosphorylates gemcitabine to its active gemcitabine-5'-triphosphate form.38 This compound, upon incorporation into DNA, results in chain termination. Increased cellular transport and increased affinity for dCK allow for greater intracellular retention and accumulation of gemcitabine as compared to cytarabine. This may account for the extended spectrum of activity seen with the newer compound.25 In addition, there is evidence that gemcitabine inhibits ribonu-cleotide reductase, leading to the depletion of cellular deoxyribonucleotide triphosphate pools. This not only depletes cells of active nucleotides essential for DNA synthesis, but also propagates the toxicity of gemc-itabine. Cells are forced to further incorporate gemc-itabine into DNA strands because of the lack of competition with normal nucleotides. Additionally, as a result of the structural conformation of gemcitabine, a normal base pair is routinely added to DNA strands just after incorporation of the toxic compound. This effectively protects gemictabine from being excised by DNA repair enzymes from the newly formed strand, and ensures cell death. This mechanism has been termed "masked chain termination."Gemcitabine has demonstrated activity in a variety of solid as well as hematologic malignancies, including Hodgkin's disease, mantle cell lymphoma, and chronic lymphocytic leukemia.38

Pharmacokinetics/metabolism: Extensive deamina-tion of gemcitabine occurs in the gastrointestinal tract; therefore, the compound is not active orally and is available only as a solution for injection. Deamination by cytidine deaminase is the primary metabolic route, which occurs in liver, plasma, and peripheral tissues. More than 90% of drug is recovered in the urine as the difluorouridine metabolite.5,19 Because of the dependence of half-life on infusion duration, many infusion schedules have been evaluated. A longer infusion duration (>70 min) is associated with a longer half-life (4-10 h) and increased clinical activity.2930

Toxicity: The dose-limiting toxicity associated with gemcitabine is myelosuppression, mainly consisting of neutropenia. Nausea and vomiting are mild. Acutely (within 6-12 h of drug administration), fever and flulike symptoms, such as headache, chills, malaise, and myalgias, are common. Elevations in hepatic transam-inases may occur and caution should be used when treating patients with underlying hepatic dysfunction.39 Mild proteinuria and hematuria have been reported frequently.519 A generalized, macropapular rash occurs in approximately 25% of patients; this is typically reversible and does not usually require discontinuation of drug.19

Fludarabine Fludarabine monophosphate is a structural analog of the purine adenine. Initially, the ara-binose analog of adenine, ara-A, was developed. However, because of the rapid inactivation by adeno-sine deaminase enzymes, the drug exhibited less than optimal antitumor activity. The addition of a fluorine atom resulted in a compound that retained antitumor activity, while resisting inactivation by deaminase enzymes.5 Thus, F-ara-A or fludarabine was developed. This compound is highly effective in the treatment of chronic lymphocytic leukemia; in addition, it has activity in acute leukemia and non-Hodgkin's lymphoma.19

Similar to cytarabine and other nucleoside analogs, fludarabine requires transport into tumor cells and activation to its triphosphate form for cytotoxic activity. The first step in this phosphorylation is performed by the enzyme dCK, which results in the active compound F-ara-ATP. This compound is active in both dividing and resting cells.40 DNA synthesis inhibition results from competitive uptake of F-ara-ATP, rather than adenine, by dividing cells for incorporation into DNA strands. Once incorporated, chain elongation is halted, inhibiting DNA synthesis. F-ara-ATP exhibits additional activity through inhibition of specific enzymes, such as DNA polymerase a, DNA ligase, and topoisomerase II.41 These actions are S-phase specific, and incorporation of fludarabine into DNA at this point in cell division is required for apoptosis. Unlike cytarabine, fludarabine is also incorporated into RNA, where it inhibits the RNA polymerase II enzyme. Subsequently, RNA transcription is terminated, and protein synthesis cannot be achieved. This may account for the activity of fludarabine in resting cells.41 Finally, evidence indicates that fludarabine may activate apoptotic pathways as well, by stimulating APAF-1, which subsequently leads to activation of caspase-9 and caspase-3 pathways.40

Pharmacokinetics/metabolism: Fludarabine is inactivated by deaminase enzymes, particularly adenine deaminase. Its terminal elimination half-life is approximately 10 h and renal excretion is the primary route of elimination.42 As excess toxicity results from accumulation of drug in renal dysfunction, dosage adjustments are recommended for patients with moderate renal dysfunction (creatinine clearance 30-70 ml/min). Fludarabine should be avoided for patients with severe renal dysfunction (creatinine clearance <30 ml/min).43

Toxicity: When fludarabine was first developed, doses were limited by neurologic toxicity. At these higher doses, a syndrome of delayed CNS toxicity was seen, characterized by paralysis and coma. It was eventually found that fludarabine could be used in lower doses, maintaining activity at less risk to the patient. For the doses used currently, severe CNS toxicity is rare.19 A small portion of patients experience some degree of neurotoxicity, which can manifest as somnolence, paresthesias, and peripheral neuropathies. The dose-limiting toxicity of fludarabine is now considered to be myelosuppression.519 42 Immunosuppression is common as well, and suppression of CD4 and CD8 cells can last up to a year before returning to normal levels. Slowly reversible, dose-dependent pulmonary toxicity consistent with interstitial pneumonitis has been reported rarely.

Antimetabolites: Folic acid analog Methotrexate Methotrexate is a unique antimetabolite that is used in a multitude of malignancies, including solid tumors, lymphomas, and lymphocytic leukemias as well as a variety of autoimmune and inflammatory disorders. This agent is the most well characterized and widely used of all the antimetabolites.

Methotrexate differs structurally from folic acid by replacement of a hydroxyl group with an amino group on the pteridine ring, as well as an additional methyl group.19 Access to the target site of action is achieved through specific intracellular transport systems, which are mediated by the reduced folate carrier and folate receptor protein. Methotrexate exerts its cytotoxic effect through inhibition of the enzyme dihydrofolate reductase (DHFR). This enzyme is responsible for converting dietary folates to their reduced or active "tetrahydro" form for use by cells in thymidylate and purine synthesis. Through binding of DHFR to methotrexate, intracellular pools of reduced folates are depleted and synthesis of DNA is prevented.5 This action can be overcome by supplying the active tetrahydro form of folate to cells exogenously; this compound is known as leucovorin or folinic acid.

Pharmacokinetics/metabolism: Oral bioavailability is variable and incomplete. Methotrexate distributes widely to tissues, including the CNS. In moderate doses, CNS levels are low; however, at high methotrex-ate doses (>1 gm/m2) therapeutic CNS levels are achieved. Methotrexate can accumulate in fluid collections, such as pleural fluid and ascites. These fluid accumulations can act as reservoirs, slowly releasing methotrexate into the bloodstream over a prolonged time course.19 Methotrexate undergoes hepatic metabolism and enterohepatic cycling to various metabolites, which are eliminated renally (filtration and active secretion). Methotrexate solubility is pH-dependent, and methotrexate can crystallize in the renal tubules at high doses.5 Alkalinization of the urine increases the solubility of methotrexate, minimizing the risk of this complication. Terminal halflife is approximately 8-10 h, but can be prolonged to over 20 h in patients with renal insufficiency, impaired enterohepatic cycling, or significant third-space fluids.19 Toxicity: The dose-limiting toxicity of methotrexate is myelosuppression. Granulocytes and platelets are the cell lines most affected. Mucositis, stomatitis, and mucosal ulceration can be severe. At higher doses, nephrotoxicity and acute renal failure can result from intratubular precipitation of drug. Hepatic toxicity is characterized by elevations in serum transaminases and bilirubin, portal fibrosis, and occasionally cirrhosis. Pulmonary toxicity is rare but potentially fatal. CNS toxicity can result from intravenous administration as well as direct intrathe-cal administration.19

ANTITUMOR ANTIBIOTICS Antitumor antibiotics: Anthracyclines, anthracene derivatives

Daunorubicin, doxorubicin, idarubicin Anthracyclines are among the most effective antineoplastic agents ever developed; the various compounds have been in use for more than 20 years (Table 101.3). They possess a wide spectrum of activity against a variety of solid tumors and hematologic malignancies and are an essential component of current therapies in AML, ALL, and Hodgkin's disease, to name a few. These compounds share an aglycone or sugar moiety attached to a four-membered anthracene ring complex, known as a chromophore. It is this chromophore that gives these drugs their intense coloring. The original anthracy-clines, doxorubicin and daunorubicin, were derived from the pigment-producing bacteria Streptomyces peucetius in the early 1960s.58

The anthracene derivatives are cell-cycle nonspecific; however, they exert the greatest activity against rapidly dividing cells. The mechanism of action of these agents is still being elucidated and remains somewhat controversial. There is evidence supporting a variety of mechanisms.58 59 Traditionally, anthracyclines have been considered intercalating agents. Because of

Common properties of anthracene and anthracenedione derivatives


Dosing information

Clinical uses

Dose adjustments

Anthracene derivatives Doxorubicin

Dose range, 40-75 mg/m2 Maximum cumulative dose,44 550 mg/m2

All, Hodgkin's disease, NHL, sarcomas, germ cell tumors, many solid tumors (breast, stomach, head/neck, liver, bladder)

Renal impairment45

Hepatic impairment46


Dose range, 45-90 mg/m2 Maximum cumulative dose,47 550 mg/m2


Renal impairment48

Hepatic impairment48


Dose range, 10-12 mg/m2 Maximum cumulative dose: doses of 150-290 mg/m2 have resulted in 5% chance of cardiomyopathy49


Renal impairment50

Hepatic impairment50'51

Anthracene-dione derivatives Mitoxantrone

Dose range, 10-15 mg/m2 Maximum cumulative dose: doses exceeding 80-120 mg/m2 have been associated with a higher incidence of cardio-myopathy52-56

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