No abstract

The purpose of this study was to evaluate the effect of early and temporal CB-154 induced suppression of prolactin secretion on the genesis of mammary tumors in female Sprague-Dawley rats treated i.g. with 3 doses of 7,12-dimethylbenzanthracene (DMBA); doses which yield a high (20 mg), moderate (5 mg) and low (1.25 mg) mammary carcinoma incidence. In addition, the effect of prolactin suppression on the genesis of mammary tumors in strains of rodents which, when treated with maximally tolerated doses of DMBA, develop a moderate (female Lewis rats) and a low (female Long-Evans rats and female Balb/c mice) mammary carcinoma incidence was also evaluated. Daily suppression of prolactin secretion during DMBA treatment (30 days before, during and 30 days after) (series 1) or commencing 30 days after DMBA treatment (for 60-81 days) (series 2) significantly (P less than 0.05) reduced the number of mammary carcinomas in Sprague-Dawley rats treated with 20 and 5 mg DMBA and in Lewis rats (series 2); treatment with CB-154 did not significantly lower mammary carcinoma incidence in Sprague-Dawley rats treated with 1.25 mg DMBA, nor in Lewis rats (series 1), Long-Evans rats and Balb/c mice. These results provide evidence that the effectiveness of prolactin suppression in the prophylaxis of chemical carcinogenesis of the rodent mammary gland is enhanced when a moderate or large dose of the carcinogen is used, or a strain of rodent is used which is moderately or highly susceptible to the mammary oncogenic effects of the carcinogen. Low doses of the carcinogen or use of a rodent strain relatively resistant to the carcinogen nullifies the chemopreventive activities of early prolactin suppression.

Daily treatment of female Sprague-Dawley rats with CB-154 (prolactin suppressor) or Tamoxifen (estrogen antagonist) for 33 days before and after 7,12-dimethylbenzanthracene (DMBA) administration reduced (p < 0.05) the incidence of mammary carcinomas by 58 and 49%, respectively. A combination of CB-154 and Tamoxifen further reduced (p < 0.05) mammary carcinoma incidence by an additional 50–59%. Treatment with Tamoxifen for 66 days beginning 33 days after carcinogen treatment reduced (p < 0.05) the incidence of mammary carcinomas by 65%; CB-154 treatment, during the same time period, did not significantly effect the final yield of mammary carcinomas. The combination of Tamoxifen and CB-154 was comparable to Tamoxifen alone in suppressing the incidence of mammary carcinomas in the latter study. These results demonstrate a substantial suppressive and synergistic effect of Tamoxifen and CB-154 in the initiating phases of mammary carcinogenesis while in the early promoting phases of this oncogenic process, short-term treatment with Tamoxifen was superior to CB-154 treatment; no synergism between these clinically important compounds was observed.

One hundred forty-seven female Sprague-Dawley rats were divided into 5 groups and at 60 days of age were treated i.g. with 5 mg of 7,12-dimethylbenzanthracene (DMBA) suspended in 1.0 ml of sesame oil. Selenium (Se), as selenium dioxide (SeO2), was administered in the drinking water to 4 of the 5 groups (30 rats/group) at 2 doses (2 and 4 mg/l) from 30-90 days of age (series 1) and from 90-150 days of age (series 2) prior to the onset of palpable mammary tumors. One group of rats (27 rats) served as controls. All rats were palpated weekly for mammary tumors and sacrificed 28 weeks after DMBA treatment. Total number of palpable mammary carcinomas which developed in each group were: controls, 60; series 1, 2 mg Se dose, 27, 4 mg Se dose, 29; series 2, 2 mg Se dose, 24, 4 mg Se dose, 32. Each dose level of Se in each series significantly (P less than 0.05) reduced the incidence of mammary carcinomas. These results provided evidence that Se can inhibit the early promoting phases of polycyclic hydrocarbon induced mammary carcinogenesis in female rats. Two hundred twenty-six nulliparous and 99 multiparous GR mice were treated daily with estrogen and progesterone for 13-16 weeks. Se (SeO2) was administered in the drinking water (2 mg/l) to one-half of these mice. Total number of mammary carcinomas in control nulliparous and multiparous mice were 119 and 90, respectively; in Se treated nulliparous and multiparous mice, 113 and 81, respectively. Se did not significantly effect mammary carcinoma incidence in hormone treated nulliparous and multiparous GR mice.

A high incidence of mammary tumors is found in multiparous GR mice during the 2nd and 3rd pregnancies and in nulliparous GR mice treated with estrone/progesterone. The purpose of this study was to determine if prolactin is a contributing hormone in the genesis of these neoplasms. In one series of experiments, 238 15-week-old nulliparous GR mice were treated with estrone (drinking water, 0.5 mg/liter) plus progesterone (30 mg progesterone pellet with cholesterol, implanted SC once monthly) for a period of 13 weeks. Half of these mice were injected SC once daily with 100 micrograms of the prolactin-suppressing drug 2-bromo-alpha-ergocryptine (CB-154) for the duration of hormone treatment, and the other half were injected SC once daily with 0.9% NaCl solution (controls). In another series of experiments, 87 pregnant GR mice were divided into two groups and injected SC once daily from day 7 to 21 of pregnancy with 0.9% NaCl solution (controls) or CB-154 (100 micrograms/mouse). In the first series, the numbers of mice with mammary tumors and total number of mammary tumors were: controls, 58/119 (49%) and 73; CB-154 treatment, 34/119 (29%) and 37, respectively. In the second series, the numbers were: controls, 39/44 (89%) and 73; CB-154 treatment, 24/43 (56%) and 43, respectively. In both studies, CB-154 treatment significantly (p less than 0.05-0.005) reduced the percentage of mice with mammary tumors and total number of mammary tumors. These results provide evidence that prolactin is a contributing hormone in the genesis of estrone/progesterone and pregnancy-induced mammary tumors in female GR mice.