Inhibitory effects of WR-2721 and cysteamine on tumor initiation in mammary glands of pregnant rats by radiation

We evaluated the effect of WR-2721 [S-2-(3-aminopropylamino)-ethylphosphoro thioic acid] and cysteamine (2-mercaptoethylamine) on the development of ra diation-induced mammary tumors in rats. Pregnant rats were treated with WR- 2721 or cysteamine 30 min prior to whole-body irradiation with gamma rays f rom a Co-60 source at a dose of 1.5 or 2.6 Gy. Additional pregnant rats wer e given saline and then exposed to gamma rays at a dose of 0, 1.5 or 2.6 Gy as a control. All rats were implanted with pellets of diethylstilbestrol, a tumor promoter, 1 month after termination of nursing and were observed fo r 1 year to detect palpable mammary tumors. No mammary tumors developed in the saline-injected nonirradiated rats. However, when rats were irradiated with 1.5 or 2.6 Gy after saline treatment, the incidence of mammary tumors was high (71.4 and 92.3%, respectively). Administration of WR-2721 or cyste amine prior to irradiation with 1.5 Gy significantly decreased the tumor in cidence (23.8 and 20.8%, respectively). Tumor prevention by either agent wa s less effective at the higher dose. The appearance of the first mammary tu mor occurred later in rats treated with WR-2721 or cysteamine than in the c ontrol rats. An increasing rate of adenocarcinoma in the control group was observed with increasing dose from 1.5 Gy up to 2.6 Gy. However, the develo pment of adenocarcinoma did not increase after pretreatment with WR-2721 or cysteamine in rats irradiated with 2.6 Gy. Many of the mammary tumors that developed in the control rats were of the ER(+)PgR(+) type. Administration of WR-2721 produced no tumors of the ER(-)PgR(+) type. Cysteamine treatmen t increased the development of ER-negative tumors. The serum concentration of progesterone was significantly higher in rats treated with WR-2721 or cy steamine than in the control rats. On the other hand, the estradiol-17 beta concentration was reduced by treatment with WR-2721, but not significantly compared to the control. WR-2721 and cysteamine had no effect on the prola ctin concentration of the irradiated rats. The results suggest that adminis tration of WR-2721 or cysteamine prior to the irradiation has a potent prev entive effect on the initiation phase during mammary tumorigenesis. (C) 200 0 Radiation Research Society.