Inhibition of PAIII Rat Prostatic Adenocarcinoma Growth and Metastasis by a New Diarylsulfonylurea Antitumor Agent, LY181984

Abstract

LY181984 4s a compound in a series of orally active diarylsulfonylureas with broad spectrum in vivo activity against syngeneic rodent and human xenograft tumor models. The PAIII rat prostatic adenocarcinoma model was used to evaluate the effects of this antitumor agent on the lymphatic and pulmonary metastasis of the tumor in male Lobund Wistar rats. LY181984 was inactive against the proliferation of PAIII cells in vitro. Following subcutaneous implantation of 106 PAIII cells in the tail, oral administration of LY181984 (25.0, 50.0, or 100.0mg./kg./day) for 30 days had no significant effects on body weight gain. LY181984 treatment produced significant (p <0.05) dose-dependent inhibition of primary tumor growth in the tail (max. inhibition = 46% from untreated control levels). In these same animals, LY181984 administration produced significant (p <0.05) dose-dependent inhibition of PAIII metastasis from the primary tumor in the tail to the gluteal and iliac lymph nodes (maximal responses = 79% and 80% from control values, respectively). PAIII metastasis to the lungs was significantly inhibited by oral LY181984 treatment. Numbers of pulmonary foci in PAIII-bearing rats were significantly (p <0.05) reduced by LY181984 administration in a dose-dependent manner (maximal reduction = 78% from control values). While the nontoxic doses (<100.0mg./kg./day for 28 days) of LY181984 produced marked decreases in tumor growth and metastasis, administration of the compound had no effect on the survival of PAIII-bearing rats. These data support the contention that LY181984 represents a new class of orally active antitumor and antimetastatic agents with potential efficacy in the treatment of hormone- insensitive prostatic cancer. Further studies are needed to define maximal efficacy of LY181984 and other sulfonylurea agents in urogenital solid tumor animal models.