Selective cell kill of the combination of gemcitabine and cisplatin in multilayered postconfluent tumor cell cultures

Both gemcitabine (2',2'-difluorodeoxycytidine, dFdC) and cisplatin (cis-dia mmine-dichloroplatinum) have significant anticancer activity against ovaria n, head and neck, and non-small cell lung cancer (NSCLC). dFdC can be incor porated into DNA and RNA, and inhibit DNA repair, while cisplatin can form Pt-DNA adducts. We previously observed schedule-dependent synergism of the combination of dFdC and cisplatin in monolayer cell cultures. We now evalua ted whether the combination would also enable selective cell kill in multil ayered postconfluent cell cultures, since each compound showed variable act ivity in multilayered cells. The combination was tested in multilayered cul tures from cell lines with a different histological origin: the human head and neck squamous cell carcinoma cell line UMSCC-22B (22B), the human NSCLC cell line H322, and ADDP, a cisplatin-resistant variant of the human ovari an cancer cell line A2780. Sensitivity of the multilayered cells was depend ent on exposure duration and sequence of the drug combinations, which were added in a constant molar ratio (dFdC:cisplatin 1:100), with a total exposu re time of 96 h. The type of interaction was related to the degree of resis tance of the cell lines to either dFdC or cisplatin. Thus, the very sensiti ve 22B cells only showed an additive effect when cells were preincubated fo r 24 h with dFdC prior to exposure to the combination. In contrast, in the resistant ADDP and H322 cells, synergism was the most common profile (three out of four schedules tested). This is of special relevance when we take i nto account that these drugs only show cytostatic effects when administered alone, whereas the combination produced cytotoxic cell killing. In conclus ion, combining dFdC with cisplatin can be at least additive, but synergisti c in multilayered postconfluent cells resistant to dFdC and cisplatin. [(C) 1999 Lippincott Williams & Wilkins.].