CAI - EFFECTS ON CYTOTOXIC THERAPIES IN-VITRO AND IN-VIVO

CAI (NSC 609974; L651582), a new agent that has demonstrated antimetas tatic activity in vitro and in vivo, was not very cytotoxic toward EMT -6 mouse mammary carcinoma cells in culture or toward FSaIIC fibrosarc oma cells in vivo. Coexposure of EMT-6 cells to CAI and antitumor alky lating agents under various environmental conditions did not markedly increase the cytotoxicity of cisplatin (CDDP), melphalan, or carmustin e (BCNU). However, the combination of CAI and 4-hydroperoxycyclophosph amide (4-HC) produced much greater than additive killing of EMT-6 cell s. CAI also increased the sensitivity of hypoxic EMT-6 cells to X-rays . CAI increased the cytotoxicity of cyclophosphamide toward FSaIIC tum or cells when animals were treated with single doses of both drugs. Th e effect of CAI on tumor cell killing by cyclophosphamide was greatest at high doses of the antitumor alkylating agent. CAI administration a ppeared to result in increased serum levels of prostaglandin E(2) and leukotriene B-4 in animals bearing the Lewis lung tumor. Administratio n of CAI on days 4-18 did not alter the growth of the Lewis lung carci noma but did result in an increase in the tumor-growth delay produced by treatment with CDDP, cyclophosphamide, melphalan, BCNU, and fractio nated radiation. Although CAI did not reduce the number of lung metast ases present in Lewis lung carcinoma-bearing mice on day 20, it did ap pear to reduce the number of large (vascularized) metastases present o n that day.