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Chapter: Modern Pharmacology with Clinical Applications: Antineoplastic Agents

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Antineoplastic Agents: Plant-Derived Products

Three classes of plant-derived drugs, the vinca alkaloids (vincristine, vinblastine, and vinorelbine), the epipodo-phyllotoxins (etoposide and teniposide), and the tax-anes (paclitaxel and taxotere), are used in cancer chemotherapy.

PLANT-DERIVED PRODUCTS

 

Three classes of plant-derived drugs, the vinca alkaloids (vincristine, vinblastine, and vinorelbine), the epipodo-phyllotoxins (etoposide and teniposide), and the tax-anes (paclitaxel and taxotere), are used in cancer chemotherapy. These classes differ in their structures and mechanisms of action but share the multidrug re-sistance mechanism, since they are all substrates for the multidrug transporter P-glycoprotein.

 

Vinca Alkaloids

Vincristine, Vinblastine, and Vinorelbine

 

Vincristine (Oncovin) and vinblastine (Velban) are both produced by the leaves of the periwinkle plant. Despite their structural similarity, there are significant differences between them in regard to clinical usefulness and toxicity.

 

The vinca alkaloids bind avidly to tubulin, a class of proteins that form the mitotic spindle during cell divi-sion. The drugs cause cellular arrest in metaphase dur-ing mitosis, and cell division cannot be completed. Although the vinca alkaloids usually have been re-garded as phase specific in the cell cycle, some mam-malian cells are most vulnerable in the late S-phase.

 

Resistance to vinca alkaloids has been correlated with a decreased rate of drug uptake or an increased drug efflux from these tumor cells. Cross-resistance usu-ally occurs with anthracyclines, dactinomycin, and podophyllotoxins.

Both vincristine and vinblastine are extensively bound to tissues, and only small amounts of the drug are distributed to the brain or CSF. The plasma disappear-ance of vinblastine and vinorelbine is triphasic. Similar clinical pharmacokinetics have been noted with vin-cristine and vinorelbine. Biliary excretion is the major route of drug excretion.

 

Vincristine is an important component of the cura-tive combination chemotherapy for acute lymphoblas-tic leukemia, Hodgkin’s disease (the MOPP regimen), and non-Hodgkin’s lymphomas. It is also used in several regimens for pediatric solid tumors, including Wilms’ tu-mor, Ewing’s sarcoma, rhabdomyosarcoma, and neu-roblastoma; in adult tumors of the breast, lung, and cervix; and in sarcomas. Its relative lack of myelosup-pression makes it more attractive than vinblastine for use in combination with myelotoxic drugs. Vinblastine is especially useful in testicular carcinomas and is also ac-tive in Hodgkin’s disease, other types of lymphomas, breast cancer, and renal cell carcinoma.

 

Vinorelbine is particularly useful in the treatment of advanced non–small cell lung cancer and can be admin-istered alone or in combination with cisplatin. It is thought to interfere with mitosis in dividing cells through a relatively specific action on mitotic microtubules.

 

Neurological toxicity is the major dose-limiting tox-icity of vincristine, whereas bone marrow toxicity is lim-iting for vinblastine. Severe neutropenia occurs in ap-proximately half of the patients receiving vinorelbine. Severe leukopenia is the major side effect of vinblas-tine. These drugs are potent local blistering agents and will produce tissue necrosis if extravasated.

 

Epipodophyllotoxins

Etoposide

 

Etoposide (VePesid) is a semisynthetic derivative of podophyllotoxin that is produced in the roots of the American mandrake, or May apple. Unlike podophyllo-toxin and vinca alkaloids, etoposide does not bind to mi-crotubules. It forms a complex with the enzyme topoiso-merase II, which results in a single-strand breakage of DNA. It is most lethal to cells in the S- and G2-phases of the cell cycle. Drug resistance to etoposide is thought to be caused by decreased cellular drug accumulation.

 

Etoposide is most useful against testicular and ovar-ian germ cell cancers, lymphomas, small cell lung can-cers, and acute myelogenous and lymphoblastic leukemia. Toxicities include mild nausea, alopecia, aller-gic reaction, phlebitis at the injection site, and bone marrow toxicity.

 

 

Teniposide

 

Teniposide (VM-26, Vumon) is closely related to etopo-side in structure, mechanisms of action and resistance, and adverse effects. It is more lipophilic and approxi-mately threefold more potent than etoposide. Its major uses have been in pediatric cancers, particularly in acute lymphoblastic leukemias.

 

Taxanes

Paclitaxel

 

Paclitaxel (Taxol) is a highly complex, organic com-pound isolated from the bark of the Pacific yew tree. It binds to tubulin dimers and microtubulin filaments, pro-moting the assembly of filaments and preventing their depolymerization. This increase in the stability of mi-crofilaments results in disruption of mitosis and cyto-toxicity and disrupts other normal microtubular func-tions, such as axonal transport in nerve fibers.

 

The major mechanism of resistance that has been identified for paclitaxel is transport out of tumor cells, which leads to decreased intracellular drug accumula-tion. This form of resistance is mediated by the mul-tidrug transporter P-glycoprotein.

 

Paclitaxel’s large volume of distribution indicates sig-nificant tissue binding. The drug is extensively metabo-lized by the liver, and doses must be reduced in patients with abnormal liver function or with extensive liver metastases. Very little of the drug is excreted in the urine.

 

Paclitaxel is among the most active of all anticancer drugs, with significant efficacy against carcinomas of the breast, ovary, lung, head, and neck. It is combined with cisplatin in the therapy of ovarian and lung carcinomas and with doxorubicin in treating breast cancer.

 

Myelosuppression is the major side effect of pacli-taxel. Alopecia is common, as is reversible dose-related peripheral neuropathy. Most patients have mild numb-ness and tingling of the fingers and toes beginning a few days after treatment. Mild muscle and joint aching also may begin 2 or 3 days after initiation of therapy. Nausea is usually mild or absent. Severe hypersensitivity reac-tions may occur. Cardiovascular side effects, consisting of mild hypotension and bradycardia, have been noted in up to 25% of patients.

 

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