title: Marked antiangiogenic and antitumor efficacy of AG3340 in chemoresistant human non-small cell lung cancer tumors: single agent and combination chemotherapy studies.
abstract: Effective therapy is needed to improve the survival of patients with advanced lung cancers. We studied the effects of a selective metalloprotease inhibitor, AG3340, on chemoresistant human non-small cell lung cancer tumors (line MV522) in vivo. Mice bearing s.c. tumors were given twice-daily oral doses 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 approximately 25% growth inhibition observed at a maximum tolerated dose of approximately 30 mg/kg/week (given i.p., twice weekly). Carboplatin inhibited tumor growth markedly only at toxic doses, demonstrating a superior therapeutic index of AG3340 to carboplatin in this tumor model. A suboptimal dose of AG3340, when used in combination with an ineffective maximum tolerated dose of carboplatin, resulted in greater tumor growth inhibitions than those produced by either agent alone. Similarly, growth inhibition was enhanced when AG3340 was used in combination with paclitaxel. Cotreatment with carboplatin did not alter AG3340 plasma concentrations achieved acutely after oral dosing. These data demonstrate an antiangiogenic and antitumor effect of AG3340 when used as a single agent and enhanced growth inhibitions when AG3340 is used in combination with cytotoxic agents. These data suggest that treatment with this novel matrix metalloprotease inhibitor may be beneficial in advanced lung cancers and other chemoresistant malignancies.
authors.affiliation: Department of Pharmacology, Agouron Pharmaceuticals, Inc., San Diego, California 92121, USA. shalinsky@agouron.com
authors.forename: D R
authors.initials: DR
authors.lastname: Shalinsky
authors.forename: J
authors.initials: J
authors.lastname: Brekken
authors.forename: H
authors.initials: H
authors.lastname: Zou
authors.forename: L A
authors.initials: LA
authors.lastname: Bloom
authors.forename: C D
authors.initials: CD
authors.lastname: McDermott
authors.forename: S
authors.initials: S
authors.lastname: Zook
authors.forename: N M
authors.initials: NM
authors.lastname: Varki
authors.forename: K
authors.initials: K
authors.lastname: Appelt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000627:therapeutic use* / Q000633:toxicity; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D016190:Carboplatin / Q000008:administration & dosage / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D009930:Organic Chemicals; D017239:Paclitaxel / Q000008:administration & dosage; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D009930:Organic Chemicals; C113282:prinomastat; D016190:Carboplatin; D017239:Paclitaxel