Marked antiangiogenic and antitumor efficacy of AG3340 in chemoresistant human non-small cell lung cancer tumors: Single agent and combination chemotherapy studies

Effective therapy is needed to improve the survival of patients with advanc ed lung cancers. We studied the effects of a selective metalloprotease inhi bitor, AG3340, on chemoresistant human non-small cell lung cancer tumors (l ine MV522) in vivo, Mice bearing s.c. tumors were given twice-daily oral do ses of AG3340, As a single agent, AG3340 inhibited angiogenesis (up to 77%) and tumor growth (up to 65%) in a dose-dependent manner at well-tolerated daily doses up to 400 mg/kg/day and induced significant tumor necrosis, In contrast, tumors were relatively insensitive to carboplatin with approximat e to 25% growth inhibition observed at a maximum tolerated dose of approxim ately 30 mg/kg/week (given i.p. twice weekly), Carboplatin inhibited tumor growth markedly only at toxic doses, demonstrating a superior therapeutic i ndex of AG3340 to carboplatin in this tumor model. A suboptimal dose of AG3 340, when used in combination with an ineffective maximum tolerated dose of carboplatin, resulted in greater tumor growth inhibitions than those produ ced by either agent alone. Similarly, growth inhibition was enhanced when A G3340 was used in combination with paclitaxel, Cotreatment with carboplatin did not alter AG3340 plasma concentrations achieved acutely after oral dos ing. These data demonstrate an antiangiogenic and antitumor effect of AG334 0 when used as a single agent and enhanced growth inhibitions when AG3340 i s used in combination with cytotoxic agents. These data suggest that treatm ent with this novel matrix metalloprotease inhibitor may be beneficial in a dvanced lung cancers and other chemoresistant malignancies.