STUDIES OF TOPOISOMERASE I INHIBITORS

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The nuclear enzyme DNA topoisomerase I relaxes supercoiled DNA and participates in DNA replication and transcription. Topoisomerase I localizes predominantly to nucleoli, and is the cytotoxic target for drugs of the camptothecin class. Several analogues of this class are currently in Phase I/II clinical trials, and early results of these traials have shown them to have activity against several types of "refractory" solid tumors. Intracellular factors reported to influence the cytotoxicity of the camptothecins include the amount of nuclear enzyme, the drug-induced increase in covalent topoisomerase I-DNA complexes, and the requirement for ongoing DNA synthesis. We suggest that additional, previously unidentified cellular events also significantly affect the cytotoxicity of the camptothecins. Therefore, we propose to test the hypotheses that: 1) Camptothecins limit their own cytotoxicity by altering the subcellular distribution of topoisomerase I and other nuclear proteins and by decreasing the amount of nuclear topoisomerase II, resulting in decreased topoisomerase I-DNA complexes and decreased DNA synthesis; 2) Intermittent, repeated exposures to the camptothecins that allow cells to maintain nuclear enzyme levels and nucleolar integrity, and consequently the ability to form topoisomerase-DNA complexes, will have the greatest cytotoxic effect; and 3) Based on biochemical observations, markers that predict the antitumor effect of topotecan in samples of primary tumors or bone marrow metatases of pediatric patients with neuroblastoma or medulloblastoma cal be identified.