Mechanisms of rolipram-induced increase in the incidence of mammary adenocarcinoma: histopathological study of a 104-week oral carcinogenicity study in female Sprague-Dawley rats

Abstract

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.