NOVEL PHOSPHONIUM SALTS DISPLAY IN-VITRO AND IN-VIVO CYTOTOXIC ACTIVITY AGAINST HUMAN OVARIAN-CANCER CELL-LINES

Phosphonium salts are part of a class of lipophilic cationic molecules that accumulate preferentially in mitochondria and inhibit the growth of human and rodent carcinoma cells in vitro and in animal models, Th e delocalized cations tested previously such as dequalinium have exhib ited considerable cross resistance against multiple drug-resistant cel ls expressing gp 170. In order to overcome this cross resistance, we h ave developed two novel phosphonium salts which contain haloalkyl moie ties with potential protein alkylating capabilities, Chloropropyltris( 4-dimethylaminophenyl)phosphonium chloride (APPCL) and 3-iodopropyltri s(4-dimethylaminophenyl)phosphonium iodide (APPI) are more lipophilic than other phosphonium salts described to date. By comparing the 50% i nhibitory concentration (IC50) values for the A2780 human ovarian carc inoma parental line to a multiple drug-resistant variant (A2780-DR), t he degree of cross resistance (IC50 for A2780-DR/IC50 for A2780 Parent al) were found to be 494 for doxorubicin, but only 2.7 for APPCL. Simi larly, the degree of cross resistance using a cisplatin-resistant vari ant (IC50 for A2780-CR/ IC50 for A2780 Parental) was 30 for cisplatin, but only 2.2 for APPCL. APPCL is also active in vitro against UCI 101 (IC50 = 80 nM), an ovarian carcinoma line isolated from a patient who had failed chemotherapy with taxol, doxorubicin, and high-dose cispla tin. The cytotoxicity of APPI was comparable to that of APPCL with an ICS, ranging from 16.7 to 83.0 nM for a panel of seven cell lines, Whe n administered intraperitoneally at a total dose of 46 mg/kg over 15 d ays, APPCL increased the median lifespan of nude mice bearing UCI 101, from a control value of 48.0 to 92.5 days (P < 0.0061). The median su rvival of the APPI-treated mice was 55 days. A total of 37.5% of the A PPCL-treated group and 12.5% of the APPI-treated group were long-term survivors: sacrifice of these mice on Day 180 and subsequent histology showed no evidence of disease. Exposure to APPCL and APPI caused mito chondrial damage to UCI 101 cells at sublethal doses in vitro, as show n by morphological damage observed with transmission electron microsco py, APPCL appears to decrease the uptake of rhodamine 123 by mitochond ria, suggesting that mitochondria may be significant targets or initia l reservoirs for this agent. In conclusion, APPI and APPCL show promis ing anticancer activity against a variety of human ovarian carcinoma c ell lines warranting further investigation. (C) 1996 Academic Press, I nc.