The central objective of this project is to develop a novel and most promising androgen-camptothecin- type analog with higher efficacy and lower toxicity for clinical use in chemotherapy of prostate cancer, with particular emphasis on improving the survival of patients with hormone-refractory prostate cancer (HRPC). A novel androgen-camptothecin analog (OL-1) consisting of a bulky linker (4-carboxyphenoxyacetic ester) and epiandrosterone group connected to camptothecin at C(20) position of E ring has been synthesized and identified as a lead drug candidate in our laboratory. Preliminary studies suggest that OL-1 shows significantly less toxicity and enhanced antitumor efficacy. The in vivo studies on tumor-bearing mice indicate that OL-1 is remarkably more effective than topotecan in controlling human prostate cancer xenografts under equitoxic conditions. Equally important, the in vivo toxicity of OL-1 in mice is 20 or 25 times lower than that of topotecan or camptothecin, respectively. Phase I studies of this project includes the synthesis of three lead novel androgen-camptothecin or topotecan or -irinotecan analogs (OL-1, OL-2, and OL-3), the formulation of these three analogs, the establishment of the analytical methods, the determination of the maximum tolerated doses (MTD) of OL-1, OL-2 and OL-3 in normal mice by the standard methods of determination of acute toxicity, and the evaluation of chemotherapeutic activity of three androgen-camptothecin-type analogs in nude mice bearing two human prostate cancer xenografts (DU-145 and PC-3) using the tumor regrowth delay assay. These specific aims are also designed to answer the question which is the selected and most promising androgen-camptothecin-type analog; how it proves to be significantly more effective in killing prostate cancer cells than topotecan; and whether its toxic side effects are dramatically less than that of topotecan. If this project is successful, a novel and most promising preclinical/clinical drug candidate will be produced. During phase II of the project the toxicity of this most promising analog in rats and dogs will be evaluated. A variety of tumor models and treatment schedules and combination therapy will be employed to further evaluate the efficacy of this most promising androgen-camptothecin-type analog. The cGMP scaled-up synthesis of this selected and most promising analog will be conducted. We will perform its in vitro and in vivo metabolism studies and pharmacokinetic study, and develop its final formulation for clinical trials. Based on our preliminary data, it can be anticipated that this most promising analog will be significantly superior to topotecan and irinotecan, providing a unique combination of improved therapeutic action in killing prostate cancers without any penalty in the form of increased drug toxicity. If therapeutic effects similar to those noted in preclinical studies could be achieved on prostate cancer patients, the clinical benefits would be substantial.
Public Health Relevance:All the preclinical studies proposed in this project will directly contribute to the design of clinical trials and the development of a novel androgen-camptothecin-type analog as a clinically useful therapeutic agent for conquering prostate cancers and reducing mortality of this disease. The development of a novel androgen-camptothecin-type drug with higher efficacy and reduced toxicity holds a considerable promise for dramatically improved therapy of prostate cancers. If therapeutic effects similar to those noted in tissue culture and in mice could be obtained in clinical trials, the benefits to prostate cancer patients would certainly be substantial.
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