Nishiyama Shoji, Okudaira Masahiko, Saito Noboru
General Toxicology Department of Toxicological Research Laboratory, Pharmaceutical Research Center, Meiji Seika Kaisha Ltd, 760 Morooka, Kohoku, Yokohama, 222-0002, Japan.
Arch Toxicol. 2006 Feb;80(2):88-97. doi: 10.1007/s00204-005-0016-6. Epub 2005 Sep 16.
The present study was carried out to elucidate the mechanisms behind an increase in the incidence of malignant or multiple mammary tumors as a result of oral administration of rolipram in a 104-week carcinogenicity study. The organs and tissues of Sprague-Dawley (SD) rats of both sexes, which had been subjected to a 104-week oral carcinogenicity study at doses of 0.2, 0.6 and 2.0 mg/kg, were examined. No treatment-related effects were seen in males; however, in females, there was a significant increase in the number of malignant or multiple mammary tumor bearers at a dose of 2.0 mg/kg. No other target organs were identified and the incidence of other tumor types were within the female control range. To clarify the mechanisms behind a rolipram-induced increase in the incidence of mammary adenocarcinoma at time points earlier than 104 weeks, the hormonal changes associated with pituitary adenoma were identified, and estrous cycling in the ovary, uterus, and vagina were examined in female rats treated with rolipram for 52 weeks. The plasma prolactin (PRL) concentration in all female groups exceeded the control value at Week 52, and all these differences were statistically significant. There was also a dose-dependent relationship with PRL-producing pituitary adenomas. Changes in estrous cycling in the uterus and vagina and a decrease in the size and number of corpora lutea in the ovaries of female rats treated with rolipram at 2.0 mg/kg for 52 weeks indicated that an increase in the estrus phase of the cycle corresponded to a marked decrease in the diestrus phase, which might result from the increased plasma estrogen concentration. Together, all of the above mentioned data suggest that rolipram not only stimulates an increase in the number and size of PRL adenomas in the pituitary gland but also in the estrus phase of the estrous cycle. These events might cause progression of the mammary gland tissues from hyperplasia to carcinoma.
在一项为期104周的致癌性研究中，为阐明口服咯利普兰导致恶性或多发性乳腺肿瘤发生率增加背后的机制，对接受0.2、0.6和2.0mg/kg剂量为期104周口服致癌性研究的雌雄Sprague-Dawley（SD）大鼠的器官和组织进行了检查。雄性大鼠未观察到与治疗相关的影响；然而，在雌性大鼠中，2.0mg/kg剂量组的恶性或多发性乳腺肿瘤携带者数量显著增加。未发现其他靶器官，其他肿瘤类型的发生率在雌性对照组范围内。为了阐明咯利普兰在早于104周的时间点导致乳腺腺癌发生率增加背后的机制，确定了与垂体腺瘤相关的激素变化，并对接受咯利普兰治疗52周的雌性大鼠的卵巢、子宫和阴道的发情周期进行了检查。所有雌性组在第52周时血浆催乳素（PRL）浓度均超过对照组值，且所有这些差异均具有统计学意义。PRL分泌性垂体腺瘤也存在剂量依赖关系。接受2.0mg/kg咯利普兰治疗52周的雌性大鼠子宫和阴道发情周期的变化以及卵巢黄体大小和数量的减少表明，发情周期中发情期的增加与动情间期的显著减少相对应，这可能是由于血浆雌激素浓度升高所致。综上所述，所有上述数据表明，咯利普兰不仅刺激垂体中PRL腺瘤数量和大小的增加，还刺激发情周期中发情期的增加。这些事件可能导致乳腺组织从增生发展为癌变。
