REGRESSION OF RAT DUNNING R-3327-H PROSTATE CARCINOMA BY TREATMENT WITH TARGETED CYTOTOXIC ANALOG OF LUTEINIZING-HORMONE-RELEASING HORMONE AN-207 CONTAINING 2-PYRROLINODOXORUBICIN

The effects of AN-207, a new targeted cytotoxic analog of LH-RH, were evalued in rats bearing hormone-dependent Dunning R-3327-H prostate ca rcinomas. AN-207 consists of the agonist [D-Lys(6)]LH-RH linked to 2-p yrrolino-doxorubicin, an intensely potent derivative of doxorubicin. I n the first experiment, 2-pyrrolinodoxorubicin was administered at a c oncentration of 50 nmol/kg, as a single drug (AN-201) and as an unconj ugated mixture with [D-Lys(6)]LH-RH or conjugated to the carrier [D-Ly s(6)]LH-RH (AN-207). Following the second administration of radical AN -201 alone or mixed with the carrier, all rats died with signs of gene ral toxicity, but all animals treated with the conjugate AN-207, survi ved. After 5 weeks of treatment with a total dose of 150 nmol/kg AN-20 7, the tumors regressed from an initial volume of 8.35 +/- 1.7 cm(3) t o 4.47 +/- 0.8 cm(3), while tumors in the control group measured 17.84 +/- 2.2 cm(3). The therapy with AN-207 also significantly reduced tum or weight and tumor burden. In the second experiment, we compared the efficacy and toxicity of 3 injections of 25 nmol/kg AN-201 or 25 nmol/ kg and 50 nmol/kg AN-207. The initial tumor volume in all groups was b etween 3.9 and 4.5 cm(3). After 5 weeks of therapy, the tumors of rats treated with 50 nmol/kg AN-207 regressed to 2.3 +/- 0.51 cm(3), where as 25 nmol/kg AN-201 was still toxic in contrast to 25 nmol/kg AN-207, while the reduction in final tumor volume was similar (6.76 +/- 1.4 c m(3) and 6.74 +/- 1 cm(3), respectively), as compared to 15.6 +/- 2.2 cm(3) for untreated animals. High capacity LH-RH receptors were found in the membranes of untreated Dunning tumor specimens, but after treat ment with AN-207, they could no longer be detected. This is the first demonstration that the new targeted cytotoxic LH-RH analog AN-207 is a n effective antitumor agent. Our work indicates that the cytotoxic ana log AN-207 is much less toxic than the antineoplastic radical (AN-201) incorporated, and significantly more active in inhibiting tumor growt h. Further development of approaches based on targeted cytotoxic analo g AN-207 may lead to major improvements in current palliative therapy of prostate cancer.