Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and etoposide are two chemotherapy agents with broad cytotoxic activity but different mechanisms of action and resistance. Previous in vitro studies of their combined cytotoxicity have yielded conflicting results. We evaluated the effects of drug scheduling in cell growth inhibition in lung and breast human cancer cell lines. A clonogenic assay with either simultaneous or sequential 24-hour incubation of paclitaxel and etoposide was used to assess growth inhibition, and the combination index was used to evaluate drug interactions. In these studies, including the A549 human lung cancer cell line, mild antagonism (combination index, > 1) was observed with concurrent exposure of paclitaxel and etoposide, but synergism (combination index, < 1) was observed when the drugs were incubated sequentially. In view of the wide range of antitumor activity of both paclitaxel and etoposide, and the potential importance and clinical impact of optimizing drug doses and schedules, we recently completed a phase I study with the following objectives: (1) to determine the maximum tolerated dose of paclitaxel given intravenously on day 10 after 10 days of oral etoposide and (2) to investigate the toxicity profile of this combination of agents. Three consecutive cohorts consisting of a total of 29 patients with various measurable or assessable tumors were treated with paclitaxel by intravenous infusion over 3 hours after receiving 10 days of etoposide 50 mg orally twice daily. Conclusions for this clinical study were that the combination was feasible and tolerable and had demonstrated antitumor activity in a group of mostly pretreated patients. The recommended doses for phase II studies were etoposide 50 mg twice daily for 10 days followed by paclitaxel 150 mg/m2 intravenously over 3 hours. A phase II study in patients with extensive small cell lung cancer, with appropriate translational studies, has been initiated.