TAXOLS AND TOPOISOMERASE-I-TARGETING AGENTS

Taxols and topoisomerase I (Topo I)-targeting agents represent the most promising new chemotherapeutic medications in the recent history of drug evaluation. Taxol is an antimicrotubular agent which stabilizes microtubules by inhibiting depolarization and arrests cells in the mitotic phase. Its major dose-limiting toxicity is leucopenia with occasional cardiac, peripheral neuropathy, and anaphylactic reactions. It has been shown to be active in refractory ovarian cancer, adriamycin-resistant breast cancer, non-small cell lung cancer, and melanoma. Topo I-targeting agents form a stable complex with topo I-DNA, suppress the relegation steps in the DNA unwinding and cause single strand break. CPT-11 and topotecan have undergone phase I and 11 clinical trials. Phase I studies suggest leucopenia is the dose-limiting side effect for both agents. CPT-11 also causes more severe and frequent watery diarrhea and pulmonary toxicity than topotecan. Initial clinical evaluations of CPT-11 from Japan show high response rate in colon cancer (46%), and non-small cell lung cancer (32%). It is also active against refractory ovarian cancer, lymphoma, and cervical cancer. Phase I studies of topotecan have demonstrated response in patients with non-small cell lung cancer and ovarian cancer. Current directions of investigations are to define optimal dose and schedule and attempt to combine with other active agents in phase II and III studies. The roles of the taxol and topo I-targeting agents in cancer therapy remain to be defined.