PubMed · 1899130
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J T MacGregor. 1991. Micronucleus assay protocols.. https://doi.org/10.1016/0165-1218(91)90116-4
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Medroxyprogesterone acetate (MPA) is currently used therapeutically in the treatment of mammary and endometrial carcinomas. In order to develop a more potent and useful drug, we synthesized the novel compound, 9alpha-fluoromedoroxyprogesterone acetate (FMPA), by fluorinating MPA, and we also previously reported that FMPA displays more potent anti-angiogenic activity in the chorioallantoic membrane assay than MPA. In the present study, we investigated (1) the effects of FMPA on rat mammary carcinomas induced by dimethylbenz[a]anthracene (DMBA) to determine the anti-tumor activity, (2) the effect on angiogenesis in rabbit corneal assays, and (3) compared these results with those for MPA. FMPA inhibited the growth of mammary carcinomas in a dose-dependent manner (7.5, 30 and 120 mg/kg). Almost complete involution of the carcinomas was observed at doses of 30 and 120 mg/kg. MPA also inhibited the growth of carcinomas at doses of 30 and 120 mg/kg, but no involution of carcinomas was observed even at 120 mg/kg. FMPA significantly and MPA to a lesser degree inhibited carcinogenesis at 120 mg/kg within their treatments. In rabbit corneal assays, FMPA significantly inhibited angiogenesis (IC50 value=0.085 microg/pellet). MPA also significantly inhibited angiogenesis (IC50 value=0.60 microg/pellet). From these results, we conclude that FMPA is potentially more effective in the treatment of mammary carcinomas than MPA.
Pregnancy is known to provide protection against 7,12 dimethylbenz[a]anthracene-(DMBA) induced mammary carcinogenesis in rats. We observed in earlier studies that splenocytes of parous rats have significant cytotoxicity against mammary tumor cells both in vitro and in vivo. However, it remains to be established how long these cytolytic cells persist after parturition in parous host. The present study was designed using parous rats, 36 or more days after parturition. We observed that fresh splenocytes from these rats had low cytolytic activity against mammary tumor cells. However, when these cells were re-stimulated with irradiated mammary tumor cells in vitro, they had significantly higher cytotoxicity against mammary tumor cells. These studies show for the first time that pregnancy induced cytotoxic splenocytes are present long after parturition and they can be restimulated in vitro to enhance the cytotoxic effect.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been observed to reduce the relative risk of breast cancer. This prompted our investigation of the chemopreventive potential of celecoxib, a specific cyclooxygenase 2 blocker, against mammary carcinogenesis induced by 7,12-dimethyl-benz(a)anthracene in female Sprague Dawley rats. Treatment with celecoxib was examined and compared to treatment with the general NSAID, ibuprofen, and to a control group receiving only dimethylbenz(a)anthracene. Dietary administration of celecoxib (1500 ppm) produced striking reductions in the incidence, multiplicity, and volume of breast tumors relative to the control group (68%, 86%, and 81%, respectively; P < 0.001). Ibuprofen also produced significant effects, but of lesser magnitude (40%, 52%, and 57%, respectively; P < 0.001). These results help confirm the chemopreventive activity of NSAIDs against breast cancer and provide the first evidence that a cyclooxygenase 2 blocking agent, celecoxib, possesses strong chemopreventive activity against mammary carcinogenesis.