The growth-inhibitory effect of 4-hydroperoxycyclophosphamide against human non-small cell lung carcinoma is enhanced by low-dose difluoromethylornithine.

Abstract

Surgically unresectable human non-small cell lung carcinoma (NSCC) is highly resistant to present chemotherapy and radiation therapy regimens. Cyclophosphamide, a potent alkylating agent, has shown some efficacy, especially in combination chemotherapy. Difluoromethylornithine (DFMO), a specific and irreversible inhibitor of ornithine decarboxylase (ODC) which produces minimal toxicity in animals and humans, has shown antiproliferative effect against human SCC in culture but a much smaller effect (cytostatic) against NSCC. We therefore investigated 4-hydroperoxycyclophosphamide (4HC) and DFMO alone and in combination against a human NSCC line (NCI-H157). Cells were treated with DFMO at graded concentrations of 0 to 800 microM from day 0 to day 7. On day 3, cells were exposed for 1 h to 4HC at graded concentrations of 0 to 80 microM, washed, and refed with media containing DFMO at initial concentrations. On day 7, cells were counted by hemacytometer. Cells treated with DFMO or 4HC alone exhibited dose-dependent growth inhibition. Growth inhibition by 4HC was enhanced through combination with DFMO. On day 7, 50 microM (5 x 10(-5) M) DFMO effected a 37% inhibition, 8 microM 4HC 47% inhibition, and the combination of 50 microM DFMO and 8 microM 4HC yielded an elevated 71% inhibition. The growth inhibitory effect and potentiating effect of DFMO were reversible upon addition of putrescine (PU) to the culture medium. The combination of DFMO and 4HC, two agents with different toxicity spectra, may represent an effective chemotherapeutic regimen for the treatment of lung cancer.