Activity of fenretinide plus chemotherapeutic agents in small-cell lung cancer cell lines

Purpose: Fenretinide [N-(4-hydroxyphenyl)retinamide, 4HPR], a synthetic ret inoid, is a potent inducer of apoptosis in small-cell lung cancer (SCLC) ce ll lines that may act through the generation of reactive oxygen species. su ggesting that it may enhance the activity of other cytotoxic agents. In lig ht of 4HPR's clinical potential and potent activity against SCLC cells, we evaluated the in vitro activity of 4HPR in combination with cisplatin, etop oside or paclitaxel. Methods: The growth-inhibitory activities of single-ag ent 4HPR, cisplatin, etoposide or paclitaxel, and combinations of 4HPR and individual chemotherapeutic agents, were evaluated using an MTT assay in tw o SCLC cell lines. Each two-drug combination was studied over a range of co ncentrations at a fixed ratio corresponding to the ratio of the IC50 values of the individual agents. Data were analyzed by median-effect analysis as previously applied to drug combination studies. Results: All four agents in hibited growth in a dose-dependent manner in the NCI-H82 and NCI-H446 SCLC cell lines. At clinically reported drug concentrations that resulted in ove r 50% growth inhibition, the activities of the combinations 4HPR and cispla tin and 4HPR and etoposide were more than additive in both cell lines, and the activity of 4HPR plus paclitaxel was more than additive in NCI-H446 cel ls. Conclusion: 4HPR's potent single-agent activity, minimal toxicity, and potential synergy with standard cytotoxic drugs will allow for the developm ent of promising investigational regimens for the treatment of patients wit h minimal toxicity, and potential synergy with standard cytotoxic drugs wil l allow for the development of promising investigational regimens for the t reatment of patients with SCLC.