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

Three aza-alkyl lysophospholipids (AALP) with related chemical structu res (BN52205, BN52218, BN52227) were examined for their anti-tumor cyt otoxic activity when used alone or in combination with TNF-alpha or CD DP. The three compounds were cytotoxic, though to a different degree, against a battery of human ovarian tumor cell lines. The compounds wer e cytotoxic to both drug sensitive and drug resistant lines and were a lso cytotoxic to an MDR(+) tumor cell line. BN52205 was the most poten t cytotoxic AALP and differed from the least cytotoxic compound BN5222 7 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 p art by free radicals as: i) treatment of the tumor cells with an inhib itor of glutathione biosynthesis, buthionine sulfoximine (BSO), augmen ted cytotoxicity and often resulted in synergy and ii) the addition of the anti-oxidant glutathione inhibited cytotoxicity. Since free radic als have also been involved in both TNF-alpha and CDDP-mediated cytoto xicity, we examined the potentiating effect of combination treatment o f AALP with these cytotoxic agents. Depending on the cell line, there was either an additive or a synergistic activity by the combination tr eatment. 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. F urther, low concentrations of AALP and TNF-alpha/drug/BSO result in ad ditive or synergistic cytotoxic activity. These findings suggest that combination treatment can be effective in the therapy of drug resistan t ovarian tumors and can achieve reduced overall toxicity.