COMBINED ACTION OF PACLITAXEL AND CISPLATIN AGAINST WILDTYPE AND RESISTANT HUMAN OVARIAN-CARCINOMA CELLS

Purpose: The combination of paclitaxel (PTX) and cisplatin (DDP) shows good clinical efficacy against ovarian cancer. In order to examine th e potential cellular basis for this, and provide leads as to how to op timize the combination, we examined the role of sequence of exposure t o PTX and DDP on cell growth in vitro. Methods: Four human ovarian car cinoma cell lines, A121, A2780/WT, A2780/DX5B and A2780/CP3, two human head and neck carcinoma cell lines, A253 and FaDu, and the human ileo cecal carcinoma cell line, HCT-8, were treated with PTX + DDP with sev en schedules: (A) 96 h exposure to PTX + DDP; (B) 24 h PTX alone, then 72 h PTX + DDP; (C) 4 h DDP alone, then 92 h PTX + DDP; (D) 24 h PTX alone, 4 h DDP alone, then 68 h drug-free; (E) 4 h DDP alone, 24 h PTX alone, then 68 h drug-free; (F) 3 h PTX alone, 1 h DDP alone, then 92 h drug-free; and (G) 1 h DDP alone, 3 h PTX alone, then 92 h drug-fre e. Each of 66 two-drug experiments included five plates (440 randomly treated wells per experiment). Cell growth was measured by the sulforh odamine B assay. The nature and the intensity of the drug interactions were assessed by fitting a seven-parameter model to data with weighte d nonlinear regression, enabling the estimation of an interaction para meter, alpha, with its standard error. Results: Overall there was very little departure from Loewe additivity: 43 experiments showed Loewe a dditivity, 10 showed Loewe antagonism, and 13 showed slight Loewe syne rgy. In vitro Loewe synergy was rare, was small when present, and repr oducible only for the A121 and HCT-8 cells exposed to schedule D (24 h PTX prior to 4 h DDP). Isobolographic analysis showed complex combine d-action surfaces with regions of local Loewe synergy and antagonism. Conclusion: It appears unlikely that the good clinical efficacy of the combination is primarily caused by a synergistic interaction at the c ellular level.