PRECLINICAL AND CLINICAL PHARMACOLOGY OF PROMISING AGENTS IN GI MALIGNANCIES

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The camptothecins are a new class of anticancer agents which target the DNA relaxing enzyme, topoisomerase I. These agents include irinotecan (CPT-11), topotecan and 9-aminocamptothecin. The camptothecins act by binding to topoisomerase I and stabilizing the enzyme in a covalent complex with DNA. This leads to the accumulation of single-strand DNA break which can be converted into double strand breaks when a DNA replication four encounters these lesions. To date, CPT-11 and topotecan have demonstrating promising anticancer activity against solid tumors including colon and ovarian cancer and 9-aminocamptothecin is currently in phase II clinical testing. Ongoing clinical trials are attempting to monitor specific drug effects at the molecular level in target tissues such as tumors and bone marrow cells in order to better understand how these agents cause their clinical effects. This vial information will hopefully allow for the design of better combinations of camptothecins with other active agents for the treatment of human cancers. We are also studying the metabolism and activation of these agents in order to try to predict their clinical effects and toxicities in individual patients. - Human Subjects & Human Tissues, Fluids, Cells, etc.