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Antitumor Efficacy in Rats of CGP 19984, a Thiazolidinedione Derivative That Inhibits Luteinizing Hormone Secretion¹

Grace Cancer Drug Center, New York State Department of Health, Roswell Park Memorial Institute, Buffalo, New York 14263 [M. M. I., P. W. S.], and Research Department, Pharmaceuticals Division, CIBA-GEIGY, Ltd., CH-4002 Basel, Switzerland [L. S.]

The antitumor efficacy and the hormonal effects of the thiazolidinedione derivative (sodium methyl{{3-methyl-2-{[5-methyl-3-(2-methylal lyl)-4-oxo-2-thiazolidinyliden]hydrazono}-4-oxo-5-thiazolidinyl}}phosphate), CGP 19984, have been studied in in vivo rat prostatic and mammary cancer models. CGP 19984 significantly inhibited growth of the androgen-dependent Dunning R3327 rat prostate adenocarcinoma. Concomitant with tumor inhibition, a significant decrease in circulating luteinizing hormone and testosterone levels was observed, suggesting that the antitumor effects of drug treatment resulted primarily from inhibition of luteinizing hormone release and subsequently decreased testosterone synthesis. Drug treatment had little effect on serum prolactin or corticosterone levels. Animals showed no adverse effects from CGP 19984 except for a modest loss of body weight. In female rats, growth of the estrogen-independent MTW-9B rat mammary tumor was also inhibited by CGP 19984 and uterine weight and tumor progesterone receptor levels were reduced. The latter suggests that CGP 19984 treatment decreases circulating estrogen in female rats. However, the inhibitory effect of CGP 19984 on the growth of the MTW-9B tumor does not appear to be mediated by the action of the drug to lower estrogen levels, since this tumor is not dependent on estrogen for growth, and lower doses of CGP 19984 were found to be equally effective in reducing uterine weight, but had no antitumor activity. The ability of CGP 19984 to suppress gonadal function and to inhibit tumor growth suggests that this drug may have potential clinical application in the treatment of both hormone-dependent and -independent prostate and breast cancers.

¹ This work was supported in part by a grant from CIBA-GEIGY, Ltd., Basel, Switzerland. A preliminary report of this work was presented at the Thirteenth International Congress of Chemotherapy in Vienna (1).

² To whom requests for reprints should be addressed.

Received 9/ 9/85. Revised 12/11/85. Accepted 12/27/85.