Akakura K, Bruchovsky N, Goldenberg S L, Rennie P S, Buckley A R, Sullivan L D
Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver Clinic, Canada.
Cancer. 1993 May 1;71(9):2782-90. doi: 10.1002/1097-0142(19930501)71:9<2782::aid-cncr2820710916>3.0.co;2-z.
Since postcastration progression of tumors to an androgen-independent state appears to be linked to the cessation of androgen-induced differentiation of tumorigenic stem cells, the authors hypothesized that the replacement of androgens at the end of a period of apoptotic regression might result in the regeneration of differentiated tumor cells with further apoptotic potential.
To determine the effect of intermittent exposure of androgens on the androgen-dependent Shionogi carcinoma, the tumor was transplanted into a succession of male mice, each of which was castrated when the estimated tumor weight became about 3 g. After the tumor had regressed to 30% of the original weight, it was transplanted into the next noncastrated male. This cycle of transplantation and castration-induced apoptosis was repeated successfully four times before growth became androgen-independent during the fifth cycle. In four of Stage C and three of Stage D patients with prostate cancer, androgen withdrawal was initiated with cyproterone acetate (100 mg/d) and diethylstilbestrol (0.1 mg/d) and then maintained with cyproterone acetate in combination with the luteinizing hormone-releasing hormone agonist, goserelin acetate (3.6 mg/month). After 6 or more months of suppression of serum prostate-specific antigen (PSA) into the normal range, treatment was interrupted for 2 to 11 months. After recovery of testicular function, androgen-withdrawal therapy was resumed when serum PSA increased to a level of about 20 micrograms/l. This cycle was repeated sequentially to a total of two to four times over treatment periods of 21 to 47 months with no loss of androgen dependence.
These results demonstrate that intermittent androgen suppression can be used to induce multiple apoptotic regressions of a tumor; they also suggest that the cyclic effects of such treatment on prostate cancer can be followed by the sequential measurement of serum PSA levels.
由于肿瘤去势后进展至雄激素非依赖状态似乎与雄激素诱导的致瘤干细胞分化停止有关，作者推测在凋亡消退期结束时补充雄激素可能会导致具有进一步凋亡潜力的分化肿瘤细胞再生。
为了确定间歇性给予雄激素对雄激素依赖的席汉氏癌的影响，将肿瘤移植到一系列雄性小鼠体内，当估计肿瘤重量达到约3 g时，对每只小鼠进行去势。当肿瘤消退至原始重量的30%后，将其移植到下一只未去势的雄性小鼠体内。这种移植和去势诱导凋亡的循环在第五个周期肿瘤生长变为雄激素非依赖之前成功重复了四次。在4例C期和3例D期前列腺癌患者中，开始使用醋酸环丙孕酮（100 mg/d）和己烯雌酚（0.1 mg/d）进行雄激素剥夺，然后用醋酸环丙孕酮联合促性腺激素释放激素激动剂醋酸戈舍瑞林（3.6 mg/月）维持治疗。在血清前列腺特异性抗原（PSA）被抑制到正常范围6个月或更长时间后，治疗中断2至11个月。睾丸功能恢复后，当血清PSA升高至约20μg/L时，恢复雄激素剥夺治疗。这个循环依次重复，在21至47个月的治疗期内总共重复两到四次，且未丧失雄激素依赖性。
这些结果表明，间歇性雄激素抑制可用于诱导肿瘤多次凋亡消退；它们还表明，这种治疗对前列腺癌的周期性影响可通过连续测量血清PSA水平来跟踪。
