ANGIOGENESIS INHIBITOR TNP-470 (AGM-1470) POTENTLY INHIBITS THE TUMOR-GROWTH OF HORMONE-INDEPENDENT HUMAN BREAST AND PROSTATE CARCINOMA CELL-LINES

The angiogenesis inhibitor O-(chloroacetyl-carbamoyl)fumagillol (TNP-4 70) showed antitumor activity in three human cancer xenograft systems. TNP-470 potently inhibited the tumor growth of hormone-independent pr ostate cancer PC-3 cells and breast cancer MDA-MB-231 cells dose depen dently at weekly s.c. doses of 50-200 mg/kg with maximum inhibition of 96 and 88% (tumor growth, 4 and 12% of that in the respective control ). In experiments of combination therapy with chemotherapeutic agents, the combination of TNP-470 (100 mg/kg) and cisplatin (5 mg/kg) showed an additive antitumor effect (from treated versus control, 38 and 22% to 5%) against PC-3 carcinoma. 5-Fluorouracil and Adriamycin alone di d not significantly inhibit MDA-MB-231 tumor growth (treated versus co ntrol, 131 and 64%, respectively). TNP-470 also inhibited tumor growth of WiDr colon cancer, although the inhibition was less marked (treate d versus control, 39%) than that observed with the hormone-independent cancers used in this study. In an in vitro study, all the cell lines tested were considerably insensitive to TNP-470 in monolayer cultures (50% inhibitory concentration, approximately 5 mug/ml), whereas TNP-47 0 inhibited the anchorage-independent growth of PC-3 and MDA-MB-231 ce lls (50% inhibitory concentration, 0.05 and 470 ng/ml, respectively). The inhibitory activity of TNP-470 against anchorage-independent growt h correlated well with the in vivo antitumor activity among the cell l ines tested. Thus, this inhibitory action may partly contribute to the potent antitumor activity of the angiogenesis inhibitor TNP-470, at l east in the case of PC-3 and MDA-MB-231. These results suggest that ho rmone-independent prostate and breast cancers may be appropriate targe t diseases for TNP-470 clinical trials.