CYTOTOXICITY OF NEW AZA-ALKYL LYSOPHOSPHOLIPIDS AGAINST DRUG-SENSITIVE AND RESISTANT HUMAN OVARIAN TUMOR-CELL LINES - ROLE OF FREE-RADICALS AND POTENTIATION OF CYTOTOXICITY BY TNF-ALPHA AND CDDP

Three aza-alkyl lysophospholipids (AALP) with related chemical structures (BN52205, BN52218, BN52227) were examined for their anti-tumor cytotoxic activity when used alone or in combination with TNF-alpha or CDDP. The three compounds were cytotoxic, though to a different degree, against a battery of human ovarian tumor cell lines. The compounds were cytotoxic to both drug sensitive and drug resistant lines and were also cytotoxic to an MDR(+) tumor cell line. BN52205 was the most potent cytotoxic AALP and differed from the least cytotoxic compound BN52227 by a substitution of a methoxy group for an ethoxy group at position 1. The AALP-mediated cytotoxicity was found to be mediated in large part by free radicals as: i) treatment of the tumor cells with an inhibitor of glutathione biosynthesis, buthionine sulfoximine (BSO), augmented cytotoxicity and often resulted in synergy and ii) the addition of the anti-oxidant glutathione inhibited cytotoxicity. Since free radicals have also been involved in both TNF-alpha and CDDP-mediated cytotoxicity, we examined the potentiating effect of combination treatment of AALP with these cytotoxic agents. Depending on the cell line, there was either an additive or a synergistic activity by the combination treatment. Furthermore, combination of BN52205 and TNF-alpha resulted in a synergistic activity against the MDR(+) ovarian line, AD10, and the cis-platinum resistant line, C30. These results demonstrate that AALP are cytotoxic to tumor cell lines and can overcome drug resistance. Further, low concentrations of AALP and TNF-alpha/drug/BSO result in additive or synergistic cytotoxic activity. These findings suggest that combination treatment can be effective in the therapy of drug resistant ovarian tumors and can achieve reduced overall toxicity.