Vinca Alkaloids

Vincristine, vinblastine, vindesine, vinorelbine

The vincas are natural compounds originally derived from the periwinkle plant. Two of these compounds, vincristine and vinblastine, are usedin the treatment of a variety of hematological malignancies, including lymphocytic leukemia, lymphoma, Hodgkin's disease, and myeloma.

Vinca alkaloids are known as "spindle poisons," because of their ability to inhibit the assembly of microtubules. This targeting of microtubules is thought to be one of the most important sites of antitumor activity discovered to date.63 These compounds act by directly binding to the "vinca domain" on tubulin, blocking its ability to polymerize into microtubules.64 Microtubules are cytoskeletal fibers, comprising tubulin subunits, which are responsible for a variety of cellular functions crucial to mitosis, including chromosomal segration and maintenance of cellular shape. Disruption of microtubule dynamics by vinca alkaloids results in absence of a mitotic spindle, which leads to irregular dispersion of chromosomes throughout the cytoplasm. Ultimately, cells are arrested during mitosis in the metaphase/anaphase transition, and apoptosis occurs. Microtubules are responsible for a variety of other cellular functions as well, including cellular transport and motility, phagocytosis, neurotransmission, and axonal transport.65 Inhibition of these nonmitotic cellular functions may account for some of the adverse effects common to the vinca alkaloids.

Pharmacokinetics/metabolism: Vinca alkaloids, as a class, are poorly absorbed from gastrointestinal tract. They are only available for intravenous administration. Distribution occurs mainly within the blood, and the compounds bind tightly to blood components. Penetration of the CNS is poor. All four compounds are metabolized extensively by the liver and excreted in the bile. Small amounts of unchanged drug are recovered in the urine. Dosage adjustments are recommended for patients with hepatic dysfunction to avoid excessive toxicity.19

Toxicity: Although vincas are structurally similar, their spectra of activity and adverse effects differ significantly. The dose-limiting toxicity of vincristine is neurotoxicity, likely due to inhibition of microtubule effects related to neuronal transmission.65 This can manifest as sensory and/or motor neuropathy and is characterized by paresthesias, palsies, and pain. Autonomic complications, such as abdominal pain, orthostatic hypotension, constipation, and paralytic ileus, may also occur. For this reason, vincristine doses have traditionally been limited to 2 mg, although recent protocols are challenging this maximum dose. Other adverse effects associated with vincristine include SIADH and alopecia. Fatal cases of intrathecal administration have been reported.66 While the potential for myelosuppression exists with vincristine, it is uncommon at standard doses. Conversely, the dose-limiting toxicity for vinblastine and vinorelbine is myelosuppression. Anemia and thrombocytopenia can occur, but leukopenia is most significant.5 Although neurotoxicity may occur, it is much less common than with vincristine. This primarily manifests as myalgias and arthralgias and occurs more commonly with vinorelbine than vinblastine.5

PODOPHYLLOTOXIN DERIVATIVES Etoposide, teniposide

Podophyllotoxin is an extract from the mandrake plant (mayberry or podophyllum). This compound is a well-known spindle poison that binds to microtubule proteins and inhibits assembly of microtubules. The podophyllotoxin derivatives, etoposide and tenipo-side, while originally developed in an effort to retain the activity of podophyllotoxin, both exert their antitumor activity through a different mechanism.567 Teniposide differs from etoposide by the addition of a sulfur-containing group in place of a methyl group on the sugar ring and is approximately 10-fold more potent than etoposide in vitro.19 These agents are active against a variety of malignancies, including small cell lung cancer, testicular cancer, leukemia, and lymphoma.

Etoposide and teniposide are thought to exert their activity by binding to topoisomerase II, forming stable ternary complexes with DNA and topoisomerase II. As a result, topoisomerase II remains bound between the free end of the cleaved DNA strand and the drug, unable to reseal the broken DNA. This ultimately results in accumulation of strand breaks and subsequent cell death.5 68 Because these compounds target the enzyme topoisomerase II, drug administration schedule is important as this enzyme is expressed only in certain phases of mitosis. Thus, continuous administration is advantageous because it maximizes the likelihood of exposing a dividing tumor cell to the drug. Indeed, one study showed this dramatic effect by comparing 1-day administration of etoposide (500 mg/m2) to 5-day administration (100 mg/m2/day) in SCLC patients. Although the same total dose of drug was administered, the response rate of the group receiving single-day infusion was 10%, while the consecutive treatment group had a response rate of 89%.69 Thus, exposing cells to lower concentrations of drug for prolonged times is thought to maximize the therapeutic effect of the topoisomerase II inhibitors.

Pharmacokinetics/metabolism: Both drugs bind significantly to plasma proteins. Etoposide is approximately 50% absorbed from the gastrointestinal tract and is available orally. Considerable pharmacokinetic interpatient variability exists with both intravenous and oral dosing.70 Etoposide and teniposide undergo extensive metabolism in the liver. It is estimated that 30-70% of etoposide is excreted renally, while this accounts for only 5-20% of teniposide elimination. Dose adjustments are recommended for patients with moderate renal dysfunction (estimated creatinine clearance <50 ml/min) in order to avoid excessive toxicity.7172 Various metabolites have been identified for both compounds, but their significance has been disputed.

Toxicity: Toxicities of the two agents are similar. The dose-limiting toxicity for both is myelosuppres-sion, which mainly manifests as leukopenia. Thrombocytopenia occurs less often and is usually not as severe.5 Reversible alopecia, mild nausea and vomiting, and stomatitis are common. Allergic reactions including anaphylaxis have been observed. These are more common with tenioposide, which is less-water soluble than etoposide. Hepatotoxicity has been reported in up to 3% of patients receiving etoposide, consisting of hyperbilirubinemia, ascites, and transaminase elevations. Secondary leukemias, including AML and APL, have been reported. Toxicity in general is enhanced in patients with low serum albumin levels because of the decreased binding of the drug and increased free levels.19

MISCELLANEOUS AGENTS L-Asparaginase

Erwinia asparaginase, pegaspargase, Escherichia coli L-asparaginase L-Asparaginase is a compound that is actually an enzyme, L-asparagine aminohydrolase. The original, most commonly used agent is derived from Escherichia coli. Other available forms include a derivative produced by Erwinia chrysanthemi and the longer-acting pegylated asparaginase (pegaspargase). L-asparaginase possesses activity against malignancies of lymphocytic origin and is mainly used in the treatment of ALL. L-Asparaginase acts by breaking down

L-Asparagine, a nonessential amino acid required by cells for protein and nucleic acid synthesis. Most cells are able to synthesize adequate supplies of asparagine on their own; however, certain malignant cells, particularly those of lymphocytic origin, lack the synthetase enzyme required for asparagine formation. These cells are particularly sensitive to the effects of L-asparaginase. By converting existing cellular supplies of asparagine to aspartic acid and ammonia, L-asparaginase quickly depletes cells of this amino acid, thus inhibiting protein synthesis.73

Pharmacokinetics/metabolism: L-Asparaginase is not absorbed orally and is available only for parenteral administration. Distribution volume approximates plasma volume, and L-asparaginase does not penetrate CNS significantly.5 Metabolism of L-asparaginase occurs through systemic degradation,74 and the drug is cleared by the reticuloendothelial system.

Toxicity: While toxicity to the bone marrow is minimal, L-asparaginase and related compounds are associated with a variety of adverse effects. Hypersensitivity reactions, including anaphylaxis, can occur immediately and have been reported in up to 43% of patients treated with the E. coli-derived compound. Because allergic reactions are more likely to occur with intravenous administration,75 asparaginase is typically given by intramuscular or subcutaneous injection. Patients who do react to E. coli-derived asparaginase may be switched to another source of drug, either pegaspargase or Erwinia asparaginase. This is associated with a high success rate and may enable the patient to complete a prescribed course of therapy. L-Asparaginase is also associated with coagulation abnormalities. It is thought that asparaginase depletes plasma proteins involved in both coagulation and fibrinolysis, including fibrinogen, factor IX, factor XI, antithrombin III, protein C, and protein S.76 77 Both bleeding and thrombosis have been reported.76-78 Pancreatitis is another complication associated with asparaginase and routine monitoring of amylase or lipase is recom-mended.579

Hydroxyurea

While hydroxyurea is not a nucleoside analog, it is generally considered to be an antimetabolite due to its similar mechanism of action to this class of drugs. Structurally, it is an analog of urea and inhibits the enzyme ribonucleotide reductase. As a result of this inhibition, ribonucleotides are prevented from being converted to the active deoxyribonucleotide forms necessary for DNA synthesis and repair. Subsequently, DNA synthesis cannot occur and cells are stranded in the S phase or the G1-S interface.19

Pharmacokinetics/metabolism: Hydroxyurea is well absorbed from the gastrointestinal tract and is available for oral administration. Bioavailability is approximately 80-100%. It is widely distributed throughout

Table101.4 Mechanisms of resistance to traditional antineoplastic agents

Chemotherapeutic class

Mechanisms of resistance

Alkylating agents

■ Mutations of p53 tumor suppressor gene

■ Decreased transport of drug by active transport mechanisms

■ Increased production of nucleophilic substances (electron donors) that bind and detoxify reactive alkyl groups

■ Increased activity of DNA repair enzymes

■ Increased metabolism of drug to inactive form81

Antimetabolites: nucleoside analogs

■ Inefficient cellular uptake and insufficient intracellular concentration of drug due to deficient transport mechanisms

■ Increased degradation of active compound by enzymes (cytidine deaminase or 5'-nucleotidase)

■ Loss of deoxycytidine kinase (dCK) gene, which converts drug to active form35,82

Antimetabolites: folic acid analog (Methotrexate)

■Saturated active transport mechanisms

■ Increased production of DHFR (dihydrofolate reductase)

■ Slower rates of thymidylate synthesis

■ Alterations in binding affinity of DHFR and methotrexate5

L-Asparaginase

■ Increased levels of enzyme asparagine synthetase within tumor cells5,19

Anthracene derivatives

■ Increased drug efflux mechanisms, such as P-glycoprotein or MDR-1

■ Decreased expression of topoisomerase II enzyme

■ Mutation of topoisomerase II enzyme81'83

Vinca alkaloids

■ Increased levels of P-glycoprotein membrane efflux pump

■ Altered expression of tubulin isotypes

■ Tubulin mutations

■ Altered expression of microtubule-regulatory proteins64,84

Podophyllotoxin derivatives

■ Amplification of MDR-1 gene mutation

■ Decreased expression of topoisomerase II enzyme

■ Mutation of topoisomerase II enzyme

■ Mutation of p53 tumor suppressor gene5,81

Hydroxyurea ■ Increased expression of ribonucleotide reductase5,19

Hydroxyurea ■ Increased expression of ribonucleotide reductase5,19

the body, with levels detected in the CNS, fluid accumulations, and breast milk. While significant interpatient variability exists, approximately 50% of hydrox-yurea is hepatically metabolized, with 50% of drug eliminated as urea and unchanged drug in urine.519

Toxicity: The dose-limiting toxicity of hydroxyurea is myelosuppression. This is often the desired therapeutic effect as well. Mild nausea and vomiting is common, which is more severe with higher doses. Finally, skin pigmentation and macropapular rash may occur80 (Table 101.4).

TREATMENT OF HEMATOLOGIC MALIGNANCIES: SUMMARY

Many valuable agents have been developed for the treatment of hematologic malignancies since the first patient with lymphoma was treated with nitrogen mustard in 1942. While these traditional agents have broad therapeutic potential and are currently considered integral components of treatment regimens for leukemias and lymphomas, they are associated with a variety of toxicities as well. Nausea and vomiting, myelosuppression, alopecia, mucositis, infertility, and carcinogenesis are just some of the adverse effects commonly associated with these compounds. This has a dramatic impact on patients' quality of life. More recently, great advances have been made in understanding the molecular biology of cancer. New therapies are being developed to specifically target only those cells exhibiting genetic mutations, thus protecting healthy cells from unnecessary toxicity. In addition, research has been done evaluating mechanisms of resistance of tumor cells to chemotherapeutic agents and compounds are being engineered to specifically block these pathways. The ultimate goal is the development of a compound that specifically targets a chromosomal abnormality, leaving healthy cells free of toxic effects and dramatically improving the quality of life of cancer patients.

100 Hair Growth Tips

100 Hair Growth Tips

100 Hair Growth Tips EVERY Balding Person Should Know. This Report

Get My Free Ebook


Post a comment