HUMAN TOPO I--AN EXPLOITABLE ANTICANCER DRUG TARGET

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The aim of this proposal is to augment the clinical development of hycamptamine and other inhibitors of human DNA topoisomerase-I by addressing aspects of the cellular biochemistry of this agent. This study will be performed in conjunction with the NCI-sponsored phase I clinical and pharmacologic trial of hycamptamine to be conducted at the M.D. Anderson Cancer Center. The specific aims of this proposal include the quantification of DNA topoisomerase-I in human tumor cells obtained from needle aspirates of accessible tumor-bearing sites. These assays will be performed using a monospecific antihuman topoisomerase-I antibody and immunoblot analysis. Secondly, the hycamptamine susceptibility of the topoisomerase-I from these biopsies will be quantitated following exposure to drug in vitro using band-depletion immunoblotting. Thirdly, the hycamptamine susceptibility of the topoisomerase-I in the patient's tumor in vivo will be quantitated by repeating the immunoblotting procedure using a second tumor biopsy obtained immediately after hycamptamine administration. Finally, we will compare the in vitro and in vivo estimates of topoisomerase-I drug susceptibility with the plasma pharmacology and clinical response. Based on the general biochemical principles to be employed, the approach developed in this trial will be applicable to subsequent Phase II trials of hycamptamine and to the development of other inhibitors of human DNA topoisomerase I and II.