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a Section of Pediatric Hematology-Oncology, Department of Pediatrics and Committee on Clinical Pharmacology; b Section of Hematology/Oncology Department of Medicine, Committee on Clinical Pharmacology, and Cancer Research Center University of Chicago, Illinois, USA
Correspondence: Mark J. Ratain, M.D., Section of Hematology/Oncology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, Illinois 60637, USA. Telephone 773-702-4400; Fax: 773-702-0963; e-mail: mjratain{at}mcis.bsd.uchicago.edu
Topoisomerase I inhibitors are a new class of anticancer agents with a mechanism of action aimed at interrupting DNA replication in cancer cells, the result of which is cell death. Most if not all Topoisomerase I inhibitors are derivatives of the plant extract camptothecin. Irinotecan (CPT-11), a semi-synthetic derivative of camptothecin, is approved in the United States for the treatment of colorectal cancer. Ongoing clinical trials with CPT-11 show a 13% to 32% response rate when it is used singly or in combination with other chemotherapeutic agents such as 5-fluorouracil. The major dose-limiting toxicities of CPT-11 are myelosuppression and a dual phase diarrhea. Topotecan is another semi-synthetic analogue of camptothecin. It is approved for use in the United States for the treatment of cisplatin refractory ovarian carcinoma. Current clinical trials suggest antitumor activity against a variety of human tumor types. There is significant interindividual variability in the plasma disposition of this drug. The main dose-limiting toxicity is myelosuppression. There are other derivatives of camptothecin, as well as new formulations of the parent plant extract, that are in various stages of clinical trials. Some of these clinical trials are aimed at increasing the therapeutic benefits of the agents when used singly or in combination with other chemotherapeutic agent(s) or treatment modalities. The dose-limiting toxicity observed in most of these clinical trials is myelosuppression.
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