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Enhanced Suppression of Tumor Growth by Combination of Angiogenesis Inhibitor O-(Chloroacetyl-carbamoyl)fumagillol (TNP-470) and Cytotoxic Agents in Mice¹

Department of Urology and Animal Facilities for Experimental Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita 010, Japan

The antitumor effect of the novel angiogenesis inhibitor O-(Chloroacetyl-carbamoyl) fumagillol, TNP-470 (TNP, s.c.), a synthetic analogue of fumagillin, was studied in combination with cytotoxic agents—mitomycin C (MMC, i.p.), Adriamycin (i.p.), cisplatin (i.p.), and 5-fluorouracil (i.p.), using B16BL6 melanoma (B16 M) and Lewis lung carcinoma in C57BL/6 mice. When the mice were treated on days 3 and 5, addition of MMC (total dose, 5 mg/kg) or 5-fluorouracil (140 mg/kg) to TNP (150 mg/kg) maximally reduced s.c. B16 M volume from 60 to 15% or from 68 to 40% of control, respectively, and addition of MMC (5 mg/kg) to TNP (150 mg/kg) reduced s.c. Lewis lung carcinoma volume from 75 to 62% of control (P < 0.02, compared to the corresponding single drug treatments). During treatment on days 3, 5, 7, 9, and 11, addition of MMC (5 mg/kg) to TNP (150 mg/kg) reduced s.c. B16 M volume from 43 to 6% of control and reduced the number of pulmonary metastasis of i.v. B16 M from 26 to 5% of control (P < 0.001). For established tumors (>5 mm in maximal diameter), addition of MMC (12–14 mg/kg), Adriamycin (15–17.5 mg/kg), or cisplatin (4 mg/kg, by one shot) to TNP (120–140 mg/kg) with a 6–7 fractionated dosing schedule reduced s.c. B16 M volume from 50 to 20, 24, or 31% of control and reduced s.c. Lewis lung carcinoma volume from 52 to 34, 27, or 34% of control, respectively (P < 0.02). The effect of combination therapy was additive and dose-dependent, and the earlier fractionated dosing schedule exerted more enhanced antitumor effects. TNP reduced the body weight by approximately 10% of control at maximum, but this toxicity was reversible and was not affected by addition of the cytotoxic agents. The results suggest that the combination of angiogenesis inhibitor TNP and standard cytotoxic agents can be a beneficial addition to the treatment of solid tumors.

¹ This work was supported in part by Grants-in-Aid (03151033 and 04557072) from the Ministry of Education, Science and Culture, Japan.

² To whom requests for reprints should be addressed, at Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010, Japan.

Received 3/23/94. Accepted 7/28/94.

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