Antitumor activity of the progesterone antagonists ZK 98.299 and RU 38.486 in the hormone-dependent MXT mammary tumor model of the mouse and the DMBA- and the MNU-induced mammary tumor models of the rat

Abstract

The antitumor activities of the antiprogesterones ZK 98.299 and RU 38.486 (RU 486) were tested in the hormone-dependent MXT(+) mammary tumor model of the mouse and the DMBA- and MNU-induced mammary tumor models of the rat. In the MXT(+)-tumor model, treatment with the two antiprogesterones (1-10 mg/kg daily) starting on day 1 after tumor implantation led to an almost complete inhibition of tumor growth identical to that accomplished with tamoxifen. Treatment of established MXT(+) tumors with ZK 98.299 (1, 10 and 50 mg/mg) resulted in a strong, dose-dependent inhibition of tumor growth. At the 10 and 50 mg doses, the effect of ZK 98.299 was superior to that of tamoxifen (4 mg/kg) and equal to that of ovariectomy and of RU 486, whereas megestrol acetate and medroxyprogesterone acetate had no significant effect. In contrast to the massive induction of cell degeneration and cytolysis in the MXT mammary tumors resulting from ovariectomy, the treatment with the two progesterone antagonists seems rather to trigger differentiation of the mitotically active polygonal tumor cells towards glandular structures and acini with secretory activity as well as towards the development of spindle-shaped necrobiotic cell populations. The weights of the ovaries were increased after therapy with ZK 98.299 and RU 486. Due to this inhibition of the negative feedback and an 'unopposed estrogen effect', uterine weight was also significantly increased. In the DMBA-induced mammary carcinoma, ZK 98.299 (10 mg/kg) caused strong tumor-inhibiting activity almost comparable to that of ovariectomy. The inhibition was very uniform and in this regard superior to RU 486. The MNU-induced mammary carcinoma of the rat was significantly inhibited by ZK 98.299, whereas RU 486 showed only a weak effect. In the light of these results antiprogesterones can be considered to be a very promising new class of mammary tumor inhibitors.