Natural antineoplastic drugs
A subclass of antineoplastic drugs known as natural products in-cludes:
· vinca alkaloids
Vinca alkaloids are nitrogenous bases derived from the periwin-kle plant. These drugs are cell cycle–specific for the M phase and include:
After I.V. administration, the vinca alkaloids are well distributed throughout the body.
Vinca alkaloids undergo moderate liver metabolism before being eliminated through different phases, primarily in stool with a small percentage eliminated in urine.
Vinca alkaloids may disrupt the normal function of the microtu-bules (structures within cells that are associated with the move-ment of DNA) by binding to the protein tubulin in the microtu-bules.
With the microtubules unable to separate chromosomes properly, the chromosomes are dispersed throughout the cytoplasm or arranged in unusual groupings. As a result, formation of the mitot-ic spindle is prevented, and the cells can’t complete mitosis (cell division).
Cell division is arrested in metaphase, causing cell death. There-fore, vinca alkaloids are cell cycle–specific for the M phase. Inter-ruption of the microtubule function may also impair some types of cellular movement, phagocytosis (engulfing and destroying micro-organisms and cellular debris), and CNS functions.
Vinca alkaloids are used in several therapeutic situations:
· Vinblastine is used to treat metastatic testicular cancer, lym-
· phomas, Kaposi’s sarcoma (the most common acquired immuno-deficiency syndrome [AIDS]–related cancer), neuroblastoma (a highly malignant tumor originating in the sympathetic nervous system), breast cancer, and choriocarcinoma.
· Vincristine is used in combination therapy to treat Hodgkin’s disease, non-Hodgkin’s lymphoma, Wilms’ tumor, rhabdomyosar-coma, and acute lymphocytic leukemia.
· Vinorelbine is used to treat non–small-cell lung cancer. Itmay also be used in the treatment of metastatic breast cancer, cisplatin-resistant ovarian cancer, and Hodgkin’s disease.
Vinca alkaloids can interact with other drugs.
§ Erythromycin may increase the toxicity of vinblastine.
§ Vinblastine decreases the plasma levels of phenytoin.
§ Vincristine reduces the effects of digoxin.
§ Asparaginase decreases liver metabolism of vincristine, increas-ing the risk of toxicity.
§ Calcium channel blockers enhance vincristine accumulation, in-creasing the tendency for toxicity. (See Adverse reactions to vin-ca alkaloids.)
Podophyllotoxins are semisynthetic glycosides that are cell cycle–specific and act during the G2 and late S phases of the cell cycle. They include:
Etoposide is effective in the treatment of testicular cancer, non-Hodgkin’s lymphoma, lung cancer, and acute leukemia. Teniposide has demonstrated some activity in treating Hodgkin’s disease, lym-phomas, and brain tumors.
When taken orally, podophyllotoxins are only moderately ab-sorbed. Although the drugs are widely distributed throughout the body, they achieve poor CSF levels.
Podophyllotoxins undergo liver metabolism and are excreted pri-marily in urine.
Although their mechanism of action isn’t completely understood, podophyllotoxins produce several biochemical changes in tumor cells.
At low concentrations, these drugs block cells at the late S or G2 phase. At higher concentrations, they arrest the cells in the G2 phase.
Podophyllotoxins can also break one of the strands of the DNA molecule and can inhibit nucleotide transport and incorporation into nucleic acids.
Etoposide is used to treat testicular cancer lymphomas, prostate cancer, and small-cell lung cancer. Teniposide is used to treat acute lymphoblastic leukemia.
Podophyllotoxins have few significant interactions with other drugs.
· Etoposide may increase the risk of bleeding in a patient taking warfarin.
· Teniposide may increase the clearance and intracellular levels of methotrexate. (See Adverse reactions to podophyllotoxins.)