modification is required in the setting of liver dysfunction.
TABLE 54–4 Natural product cancer chemotherapy drugs: Clinical activity and toxicities.
Drug Mechanism of Action Clinical Applications Acute Toxicity Delayed Toxicity
Bleomycin Oxygen free radicals bind Hodgkin’s and non-Hodgkin’s Allergic reactions, Skin toxicity, pulmoto DNA causing singleand lymphoma, germ cell cancer, head fever, hypotension nary fibrosis, mucositis, double-strand DNA breaks and neck cancer alopecia
Daunorubicin Oxygen free radicals bind AML, ALL Nausea and vomit-Cardiotoxicity (see to DNA causing singleand ing, fever, red urine text), alopecia, double-strand DNA breaks;
Doxorubicin Oxygen free radicals bind to DNA causing singleand double-strand DNA breaks; inhibits topoisomerase II; intercalates into DNA
Etoposide Inhibits topoisomerase II Breast cancer, non-small cell lung Hypersensitivity Neurotoxicity, fluid retencancer, prostate cancer, gastric cancer, tion, myelosuppression head and neck cancer, ovarian cancer,
Breast cancer, Hodgkin’s and non-Hodg-Nausea, red urine Cardiotoxicity (see text), kin’s lymphoma, soft tissue sarcoma, (not hematuria) alopecia, myelosuppresovarian cancer, non-small cell and small sion, stomatitis cell lung cancer, thyroid cancer, Wilms’ tumor, neuroblastoma
ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CML, chronic myelogenous leukemia.
Vincristine is another alkaloid derivative of Vinca rosea and is closely related in structure to vinblastine. Its mechanism of action, mechanism of resistance, and clinical pharmacology are identical to those of vinblastine. Despite these similarities to vinblastine, vincristine has a strikingly different spectrum of clinical activity and safety profile, which results, in large part, from its higher affinity for axonal microtubules.
Vincristine has been effectively combined with prednisone for remission induction in acute lymphoblastic leukemia in children. It is also active in various hematologic malignancies such as Hodgkin’s and non-Hodgkin’s lymphomas, and multiple myeloma, and in several pediatric tumors including rhabdomyosarcoma, neuroblastoma, Ewing’s sarcoma, and Wilms’ tumor.
The main dose-limiting toxicity is neurotoxicity, usually expressed as a peripheral sensory neuropathy, although autonomic nervous system dysfunction with orthostatic hypotension, urinary retention, and paralytic ileus or constipation, cranial nerve palsies, ataxia, seizures, and coma have been observed. While myelosuppression occurs, it is generally milder and much less significant than with vinblastine. The other adverse effect that may develop is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
Vinorelbine is a semisynthetic derivative of vinblastine whose mechanism of action is identical to that of vinblastine and vincristine, ie, inhibition of mitosis of cells in the M phase through inhibition of tubulin polymerization. This agent has activity in NSCLC, breast cancer, and ovarian cancer. Myelosuppression with neutropenia is the dose-limiting toxicity, but other adverse effects include nausea and vomiting, transient elevations in liver function tests, neurotoxicity, and SIADH.