Induction of uterine leiomyomas in mice by medroxalol and prevention by propranolol.
Medroxalol hydrochloride is an antihypertensive agent with beta 1 adrenergic cardiac blocking properties, and beta 2 and some alpha 1 vasodilating activity. In previous carcinogenicity studies medroxalol was shown to induce leiomyomas of the uterus in CD-1 mice but not in Long Evans rats. In addition, there was a significant increase in endometrial stromal sarcomas in mice receiving the lowest dose of medroxalol; however, the lack of a dose response made the relationship to treatment questionable. Because of these findings, additional 18-month drug diet studies were conducted in 3 parallel segments using female CD-1 mice to determine the effects of: 1) an expanded range of doses, 2) various durations of dosing, and 3) the effect of the beta-blocker, propranolol, on leiomyoma induction. These studies confirmed the fact that chronic dietary treatment with medroxalol can lead to an increased incidence of leiomyomas in the mouse uterus, but failed to demonstrate any relationship between endometrial stromal sarcomas and medroxalol administration. A linear trend occurred in the incidence of leiomyomas and of smooth muscle hypertrophy/hyperplasia, a possible precursor to leiomyoma. Both findings were notably increased at 250 mg/kg/day or more. Doses of 50 mg/kg/day or less were considered no effect levels. At 500 mg/kg/day a treatment period of 12 months or more was required before a noticeable increase in leiomyomas occurred in mice examined after 18 months. The beta-blocker, propranolol, prevented this increase in leiomyomas, and led to the conclusion that the beta 2 agonist activity of medroxalol was involved in their induction. Propranolol did not block the spontaneous occurrence of these tumors.
Merrell Dow Research Institute, Merrell Dow Pharmaceuticals, Cincinnati, Ohio 45215.
J P
JP
Gibson
D M
DM
Sells
H C
HC
Cheng
L
L
Yuh
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000633:toxicity*; D005260:Female; D007889:Leiomyoma / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D009130:Muscle, Smooth / Q000473:pathology; D011433:Propranolol / Q000627:therapeutic use*; D014594:Uterine Neoplasms / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control
D004983:Ethanolamines; C024892:medroxalol; D011433:Propranolol