Ba. Teicher et al., POTENTIATION OF CYTOTOXIC CANCER THERAPIES BY TNP-470 ALONE AND WITH OTHER ANTI-ANGIOGENIC AGENTS, International journal of cancer, 57(6), 1994, pp. 920-925
The ability of TNP-470, a synthetic analog of fumagillin which has bee
n described as an anti-angiogenic agent, to potentiate cytotoxic cance
r therapies was investigated in vivo in the murine FSallC fibrosarcoma
and the Lewis lung carcinoma. TNP-470 was more toxic toward FSallC tu
mor cells from tumors treated in vivo than toward bone-marrow CFU-GM f
rom the same animals. TNP-470 had a dose-modifying effect on the toxic
ity of cyclophosphamide toward FSallC tumor cells which amounted to an
8-fold increase in tumor-cell killing at a cyclophosphamide does of 5
00 mg/kg. Treatment with TNP-470 and minocycline increased the permeab
ility of the FSall fibrosarcoma in vivo to the fluorescent dye Hoechst
33342 and increased the killing of both the brignt and the dim tumor
cells by cyclophophamide. TNP-470, especially in combination with mino
cycline, formed a highly effective modulator combination for treatment
of the Lewis lung carcinoma with cytotoxic cancer therapies against p
rimary and metastatic disease. The combination of TNP-470/minocycyline
and cyclophosphamide led to 40 to 50% long-term survivors in Lewis-lu
ng-carcinoma-bearing animals. Our results indicate that the use of ant
i-angiogenic modulators in cancer therapy is a very promising area for
further study. (C) 1994 Wiley-Liss, Inc.