) This application proposes a study of enhancement of paclitaxel (PCL) chemotherapy with cyclosporin A (CSA) in non-small cell lung cancer and is submitted in response to RFA CA-95-012, investigator grants for clinical cancer therapy research. Lung cancer is the leading cause of cancer death among both men and women in the United States. In 1994, over 150,000 new cases of lung cancer were diagnosed in the United States. Most patients present with advanced disease that cannot be cured surgically. Of those whose tumors are resected, the majority develop recurrent or metastatic disease to which they eventually succumb. Unfortunately, chemotherapy for advanced or metastatic lung cancer remains poorly effective. Although response rates of 30-40% are now common, response durations are short and cure is rarely if ever achieved. It is evident, therefore, that novel effective systemic therapies for lung cancer would benefit tens of thousands of patients annually. Preliminary data show that cyclosporin A enhances the efficacy of PCL against murine and human lung cancers in in vitro and against murine leukemia in vivo. Both drugs can alter cytokine gene expression in these same tumors in vitro. This proposal is designed to: (1) determine the mechanisms by which cyclosporin enhances PCL cytotoxicity in vitro by evaluating drug transport, tubulin binding, and alterations in cytokine gene expression; (2) extend the observation that cyclosporin enhances PCL cytotoxicity in vivo to fresh human lung cancer xenotransplants by means of the subrenal capsule assay; and (3) perform a phase II clinical trial of cyclosporin/PCL in previously untreated patients with non-small cell lung cancer. The results obtained from the proposed studies will contribute to development of more effective chemotherapy for lung cancer and will further understanding of the biology of this devastating tumor.
