Paclitaxel blocks cells in G2-M, and this may result in a schedule-dependent effect on paclitaxel cytotoxicity. To test this hypothesis, we evaluated paclitaxel cytotoxicity in 28 human lung cancer cell lines. Fourteen of the cell lines were derived from patients with non-small cell lung cancer (NSCLC), and 14 were from patients with small cell lung cancer (SCLC). All cell lines were exposed to a range of paclitaxel concentrations for durations of 3, 24, and 120 h, and cytotoxicity was measured with a tetrazolium-based assay. The median IC50 values for all 28 cell lines at exposure durations of 3, 24, and 120 h were >32 microM, 23 microM, and 0.38 microM, respectively. The median IC50 values for the NSCLC cell lines were >32 microM, 9.4 microM, and 0.027 microM at exposure durations of 3, 24, and 120 h, respectively. For the 14 SCLC cell lines, the median IC50 values were >32 microM, 25 microM, and 5.0 microM, respectively. Five of the 14 SCLC cell lines had IC50 values at 120 h of paclitaxel exposure that were 1000-fold less than the remaining SCLC cell lines. The median IC50 values for these five sensitive SCLC cell lines at 3-, 24-, and 120-h exposures were >32 microM, 23 microM, and <0.0032 microM, respectively. These in vitro cytotoxicity results were independent of the paclitaxel diluent, a 1:1 solution of ethanol and Cremophor EL. We conclude that longer durations of paclitaxel exposure result in an increase in the chemosensitivity of some human lung cancer cell lines and that this phenomenon is more consistent within NSCLC cell lines than in SCLC cell lines.