Small cell lung cancer (SCLC) responds to treatment with cisplatin and etoposide, but relapse is rapid and survival rates are low. Our aims were to determine the mechanisms of resistance and the potential for paclitaxel (Taxol) to overcome any drug or radiation resistance. To mimic clinical treatment, H69 SCLC cells, representative of the classic form of the disease, and H82 cells, with the phenotype of the more resistant variant disease, were treated intermittently with 100 ng/ml cisplatin or 500 ng/ml etoposide (approximate IC50drug doses) to produce stable sublines. Drug and radiation resistance were determined using the MTT assay. Protein expression was determined by Western blot. The effect of paclitaxel on drug resistance was determined by cytotoxicity assays. Intermittent 4-day treatment with 100 ng/ml cisplatin caused 2- to 3-fold resistance to cisplatin (n=5;p<0.05), and 2- to 5-fold cross resistance to etoposide, alkylating drugs, the Vinca drugs and radiation. Resistance was mediated primarily by changes in glutathione metabolism and was not associated with changes in MRP2 transport protein. Treatment with etoposide (500 ng/ml) produced cells with 2-fold resistance to etoposide (n=5;p<0.05). Cross-resistance was limited and mediated by decreased topoisomerase II&agr;. Treatment of both drug-resistant sublines with a maximal non-cytotoxic dose of paclitaxel sensitized them to other drugs and to radiation, although this treatment had no effect on the parental H69 or H82 cells. We conclude that paclitaxel may play an important role in the treatment of refractory SCLC.