PNU 145156E (formerly FCE 26644) is a noncytotoxic molecule whose antitumor activity is exerted through the formation of a reversible complex with growth/angiogenic factors, thus inhibiting their induction of angiogenesis. We studied in vitro and in vivo the activity of PNU145156E in combination with the four cytotoxic drugs doxorubicin, cyclophosphamide, methoxymorpholinyldoxorubicin (MMDX, FCE 23762, PNU152243), and 9-aminocamptothecin against M5076 murine reticulosarcoma. In vitro, PNU 145156E did not modify the cytotoxicity of the four drugs or the cell-cycle block induced by doxorubicin. In vivo, at the optimal dose of each compound, the antitumor activity was significantly increased in all combinations, with no associated increase in general toxicity being observed. In healthy mice treated with cyclophosphamide or doxorubicin the association with PNU 145156E did not enhance the myelotoxic effect induced by the two cytotoxics. These results indicate that two drugs affecting solid tumor growth through two different mechanisms-growth factor blockage and cell proliferation can be combined, resulting in increased antitumor efficacy with no additive toxicity.