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Experimental Therapeutics |
Johns Hopkins University, Baltimore, Maryland 21231 [D. J. G., J. L., J. T. I.], Kyowa-Hakko Kogyo Co., Ltd., Tokyo, Japan [C. M.], and Cephalon, Inc., West Chester, Pennsylvania 19380 [C. A. D., J. J., T. A.]
The indolocarbazole analogue CEP-751 is a potent and selective tyrosine kinase inhibitor of the neurotrophin-specific trk receptors that has demonstrated antitumor activity in nine different models of prostate cancer growth in vivo. In the slow-growing, androgen-sensitive Dunning H prostate cancers, which express trk receptors, CEP-751 induced transient regressions independent of effects on cell cycle. Because androgen ablation is the most commonly used treatment for prostate cancer, we examined whether the combination treatment of CEP-751 with castration would lead to better antitumor efficacy than either treatment alone. For a 60-day period, H tumor-bearing rats received treatment with either castration, CEP-751 (10 mg/kg once a day s.c. for 5 days every 2 weeks), a combination of both, or vehicle. Castration caused tumor regression, followed by tumor regrowth in 4–6 weeks, whereas intermittent CEP-751 treatments resulted in tumor regressions during each treatment, which were followed by a period of regrowth between intermittent drug treatment cycles. Overall, both monotherapies significantly inhibited tumor growth compared with the vehicle-treated control group. However, the combination of castration and concomitant CEP-751 produced the most dramatic results: significantly greater tumor regression than either therapy alone, with no signs of regrowth. A related experiment using an orally administered CEP-751 analogue (CEP-701), as the trk inhibitor, and a gonadotrophin-releasing hormone agonist, Leuprolide, to induce androgen ablation demonstrated similar results, indicating that these effects could be generalized to other forms of androgen ablation and other trk inhibitors within this class. In addition, when CEP-701 was given sequentially to rats bearing H tumors, which were progressing in the presence of continuous androgen ablation induced by Leuprolide, regression of the androgen-independent tumors occurred. In summary, these data demonstrate that CEP-751 or CEP-701, when combined with surgically or chemically induced androgen ablation, offer better antitumor efficacy than either monotherapy and suggest that each therapy produces prostate cancer cell death through complementary mechanisms.
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