Meistrich M L, Wilson G, Ye W S, Kurdoglu B, Parchuri N, Terry N H
Department of Experimental Radiotherapy, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Cancer Res. 1994 Feb 15;54(4):1027-34.
Procarbazine produces long-term sterility in the male by killing stem spermatogonia. The degree and selectivity of protection of stem spermatogonia in rats from procarbazine by pretreatment with steroid hormones were investigated. Male LBNF1 rats were treated for 6 weeks with Silastic implants containing testosterone plus 17 beta-estradiol. The hormone-treated rats and sham-treated controls were given a single injection of graded doses of procarbazine and the hormone implants were removed the next day. Spermatogonial stem cell survival and function, assessed by the repopulation indices and sperm head counts 10 weeks later, showed that stem spermatogonia were protected by testosterone plus 17 beta-estradiol treatment from the toxic effects of procarbazine with a dose-modifying protection factor of about 2.5. In contrast, there was no hormonal protection from the procarbazine-induced killing of differentiating spermatogonia, preleptotene spermatocytes, and spermatocytes in meiotic prophase or from the delay in maturation of round spermatids, assessed 9 days after procarbazine injection by histological or flow cytometric methods. In addition, there was no hormonal protection from the procarbazine-induced decline in body weights and lymphocyte counts, indicating that the gastrointestinal, neurological, and hematological systems were not protected. The specificity of protection indicates that the hormonal protection of the stem spermatogonia is not the result of a systemic or overall testicular decrease in drug delivery, decrease in bioactivation, nor increase in drug detoxification, except possibly within the stem cells themselves. We conclude that the degree of hormonal protection and its specificity would be appropriate for clinical application provided that the mechanism of protection is elucidated and appears applicable to humans.
丙卡巴肼通过杀死精原干细胞导致雄性长期不育。研究了用甾体激素预处理对大鼠精原干细胞免受丙卡巴肼影响的保护程度和选择性。雄性LBNF1大鼠用含睾酮加17β-雌二醇的硅橡胶植入物处理6周。给激素处理的大鼠和假处理的对照单次注射分级剂量的丙卡巴肼，并于次日取出激素植入物。10周后通过再殖指数和精子头部计数评估精原干细胞的存活和功能，结果显示，睾酮加17β-雌二醇处理可保护精原干细胞免受丙卡巴肼的毒性作用，剂量修正保护因子约为2.5。相比之下，对于丙卡巴肼诱导的分化型精原细胞、前细线期精母细胞和减数分裂前期精母细胞的杀伤，或对圆形精子细胞成熟延迟（丙卡巴肼注射9天后通过组织学或流式细胞术方法评估），没有激素保护作用。此外，对于丙卡巴肼诱导的体重和淋巴细胞计数下降也没有激素保护作用，这表明胃肠道、神经系统和血液系统未得到保护。保护的特异性表明，精原干细胞的激素保护不是药物递送的全身性或总体睾丸性降低、生物活化降低或药物解毒增加的结果，可能除了干细胞自身内部之外。我们得出结论，只要保护机制得以阐明且似乎适用于人类，激素保护的程度及其特异性将适用于临床应用。
