Martin G, Melito G, Rivera E, Levin E, Davio C, Cricco G, Andrade N, Caro R, Bergoc R
Laboratorio de Radioisótopos, Cátedra de Física, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina.
Cancer Lett. 1996 Feb 27;100(1-2):227-34. doi: 10.1016/0304-3835(95)04091-9.
The effect of tamoxifen (TAM) was evaluated on a mammary tumor model induced in Sprague-Dawley rats by intraperitoneal administration of three N-nitroso-N-methylurea (NMU) doses. Animals received TAM (1 mg/kg per day) from 10 days before the first NMU dose up to 140 days later. Thereafter, treatment was discontinued and the observation period was extended 60 days longer. Mean overall latency period, tumor number per rat and tumor incidence were recorded. Significant differences between treated and control batches were observed in tumor number per rat (1.8 +/- 1.1 versus 5.2 +/- 1.6; P < 0.05) and in tumor incidence (50% versus 100%; P < 0.05), respectively. No significant difference in latency period between both batches was recorded. All lesions induced in the control batch were malignant, whereas only 45% of those induced in TAM-treated animals were malignant and the remaining 55% were preneoplastic. At 60 days after treatment discontinuance, tumor incidence increased to 90% and also tumor number per rat increased to 4.6 +/- 1.5. TAM effect was also evaluated in rats with NMU-induced tumors by treatment with 1 mg/kg per day during 60 days starting when tumors reached a 1.5-cm diameter. Regression to less than 80% of initial size in 49% of the tumors was observed, while in ovariectomized rats, 33% of tumors regressed. Estrogen receptor content, ER (fmol/mg protein) and Kd (nM) in control tumors were: 56 +/- 10 and 0.5 +/- 0.1. In tumors of TAM-treated animals, ER was less than 5 fmol/mg protein. Findings demonstrate that TAM significantly decreased the appearance of tumors induced in rats by i.p. injection of NMU and when TAM treatment was initiated after tumor induction, some tumors failed to respond to hormonal manipulation. Differential tumor growth response after TAM or oophorectomy in each tumor indicates that in the same rat it is possible to distinguish hormone-dependent and hormone-autonomous tumor populations. Hormonal regulation of tumor growth can be under intrinsic control, regardless of the hormonal status of the whole organism.
通过腹腔注射三种剂量的N-亚硝基-N-甲基脲（NMU），在斯普拉格-道利大鼠中诱导建立乳腺肿瘤模型，评估他莫昔芬（TAM）的作用。动物在首次注射NMU前10天开始接受TAM（每天1mg/kg），持续至首次注射NMU后140天。此后，停止治疗，观察期延长60天。记录平均总潜伏期、每只大鼠的肿瘤数量和肿瘤发生率。在每只大鼠的肿瘤数量（1.8±1.1对5.2±1.6；P<0.05）和肿瘤发生率（50%对100%；P<0.05）方面，治疗组和对照组之间观察到显著差异。两组之间的潜伏期没有记录到显著差异。对照组诱导的所有病变均为恶性，而TAM治疗组诱导的病变中只有45%为恶性，其余55%为癌前病变。在停止治疗60天后，肿瘤发生率增加到90%，每只大鼠的肿瘤数量也增加到4.6±1.5。当肿瘤直径达到1.5cm时，从开始的60天内每天用1mg/kg的剂量对患有NMU诱导肿瘤的大鼠进行TAM治疗，评估TAM的作用。观察到49%的肿瘤缩小至初始大小的80%以下，而在去卵巢大鼠中，33%的肿瘤缩小。对照肿瘤中的雌激素受体含量、ER（fmol/mg蛋白）和Kd（nM）分别为：56±10和0.5±0.1。在TAM治疗动物的肿瘤中，ER小于5fmol/mg蛋白。研究结果表明，TAM显著降低了腹腔注射NMU诱导的大鼠肿瘤的出现，并且当肿瘤诱导后开始TAM治疗时，一些肿瘤对激素调节无反应。每个肿瘤在TAM或卵巢切除术后的不同生长反应表明，在同一只大鼠中可以区分激素依赖性和激素自主性肿瘤群体。肿瘤生长的激素调节可能受内在控制，而与整个机体的激素状态无关。
