Potentiation of medroxyprogesterone acetate antineoplastic activity by histidine in rat mammary tumours

The antitumour activity of arginine, histidine and medroxyprogesterone acetate (MPA) was studied in female rats with dimethylbenzanthracene (DMBA)-induced mammary adenocarcinomas. After 15 days of treatment, regression was observed in 4 of 19 (21%), 3 of 18 (16.7%) and 22 of 59 (37.3%) tumours taken from rats given arginine, histidine or MPA, respectively. A total of 17 rats with tumours that had been non-responsive to MPA were then treated with MPA plus histidine for 15 more days; the growth of 3 lesions (17.6%) was arrested, and 5 tumours (29.4%) regressed markedly. The antineoplastic activity of MPA was found to be related to the oestrogen-(ER) and progesterone-receptor (PgR) concentrations measured in the tumours before the start of treatment, whereas that of arginine and histidine appeared to be independent of receptor status. A significant reduction in serum prolactin (PRL) levels occurred in rats that were responsive to MPA alone or to MPA plus histidine. In tumours taken from the same rats, the PRL receptor content was also significantly increased in comparison with that in non-responsive tumours. In contrast, serum PRL levels increased significantly in rats with tumours that were non-responsive to MPA, whereas no change in serum PRL or PRL receptor levels was observed in rats treated with arginine or histidine. Histidine showed the ability to increase the number of ERs and PgRs in responsive tumours; this could have been responsible for the unexpected potentiation of MPA antineoplastic activity. In contrast, the levels of ER and PgR in uteri taken from the same rats were not modified. Furthermore, the addition in vitro of histidine to cytosols obtained from tumours of control animals did not influence ER and PgR concentrations. These results suggest that the effect of histidine on ER and PgR levels is probably specific for tumour tissue and is not due to a direct activity.