Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854.
Med Res Rev. 2015 May;35(3):554-85. doi: 10.1002/med.21333. Epub 2014 Dec 22.
Due to the propensity of relapse and resistance with prolonged androgen deprivation therapy (ADT), there is a growing interest in developing non-hormonal therapeutic approaches as alternative treatment modalities for hormone refractory prostate cancer (HRPC). Although the standard treatment for HRPC consists of a combination of ADT with taxanes and anthracyclines, the clinical use of chemotherapeutics is limited by systemic toxicity stemming from nondiscriminatory drug exposure to normal tissues. In order to improve the tumor selectivity of chemotherapeutics, various targeted prodrug approaches have been explored. Antibody-directed enzyme prodrug therapy (ADEPT) and gene-directed enzyme prodrug therapy (GDEPT) strategies leverage tumor-specific antigens and transcription factors for the specific delivery of cytotoxic anticancer agents using various prodrug-activating enzymes. In prostate cancer, overexpression of tumor-specific proteases such as prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) is being exploited for selective activation of anticancer prodrugs designed to be activated through proteolysis by these prostate cancer-specific enzymes. PSMA- and PSA-activated prodrugs typically comprise an engineered high-specificity protease peptide substrate coupled to a potent cytotoxic agent via a linker for rapid release of cytotoxic species in the vicinity of prostate cancer cells following proteolytic cleavage. Over the past two decades, various such prodrugs have been developed and they were effective at inhibiting prostate tumor growth in rodent models; several of these prodrug approaches have been advanced to clinical trials and may be developed into effective therapies for HRPC.
由于长期雄激素剥夺疗法（ADT）会导致复发和耐药，因此人们越来越感兴趣开发非激素治疗方法作为激素难治性前列腺癌（HRPC）的替代治疗方法。虽然 HRPC 的标准治疗方法是 ADT 联合紫杉烷和蒽环类药物，但化疗药物的临床应用受到非特异性药物暴露于正常组织引起的全身毒性的限制。为了提高化疗药物的肿瘤选择性，已经探索了各种靶向前药方法。抗体导向酶前药治疗（ADEPT）和基因导向酶前药治疗（GDEPT）策略利用肿瘤特异性抗原和转录因子，使用各种前药激活酶将细胞毒性抗癌剂特异性递送至肿瘤。在前列腺癌中，过度表达肿瘤特异性蛋白酶，如前列腺特异性抗原（PSA）和前列腺特异性膜抗原（PSMA），被用于选择性激活设计用于通过这些前列腺癌特异性酶的蛋白水解激活的抗癌前药。PSMA 和 PSA 激活的前药通常包含与通过接头偶联的有效细胞毒性剂的工程化高特异性蛋白酶肽底物，用于在蛋白水解切割后在前列腺癌细胞附近快速释放细胞毒性物质。在过去的二十年中，已经开发了各种这样的前药，它们在啮齿动物模型中有效抑制前列腺肿瘤生长；其中一些前药方法已推进到临床试验阶段，并可能开发成为 HRPC 的有效治疗方法。
