CYCLOOXYGENASE AND LIPOXYGENASE INHIBITORS AS MODULATORS OF CANCER THERAPIES

Like many clinical non-small-cell lung cancers, the Lewis lung carcino ma produces prostaglandins. The Lewis lung carcinoma was used as a mod el of both primary and metastatic disease to assess the ability of cyc looxygenase inhibitors (mefenamic acid, diflunisal, sulindac, and indo methacin), the collagenase inhibitor minocycline, and the lipoxygenase inhibitor phenidone to act as modulators of cytotoxic cancer therapie s. Although none of the single modulators given i.p. daily on days 4-1 8 altered tumor growth or the number of metastases found on day 20, mo dulator combinations consisting of minocycline/a cyclooxygenase inhibi tor and, especially, of phenidone/a cyclooxygenase inhibitor resulted in modest tumor growth delay and a decreased number of lung metastases on day 20. The most effective modulators of cisplatin (CDDP) were phe nidone/sulindac and phenidone/indomethacin, which led to 2.4- to 2.5-f old increases in the tumor growth delay produced by CDDP. The most eff ective modulations of cyclophosphamide resulted from administration of minocycline, minocycline/sulindac, or phenidone/sulindac and led to 2 .0- to 2.1-fold increases in tumor growth delay by cyclophosphamide. T he most effective modulators of melphalan produced 4.5- to 4.7-fold in creases in tumor growth delay by the drug and were minocycline/sulinda c, minocycline/mefenamic acid, and phenidone/sulindac. The most effect ive modulation of carmustine (BCNU) was obtained with minocycline/suli ndac and minocycline/diflunisal leading to 2.8- to 3.1-fold increases in tumor growth delay by BCNU. Finally, the most effective modulation of radiation was obtained with minocycline/sulindac and phenidone/suli ndac and resulted in 2.8- to 3.3-fold increases in tumor growth delay by radiation. The modulator combination that along with the cytotoxic therapies was most effective against metastatic disease was phenidone/ mefenamic acid. There was no clear relationship between effective modu lation of the cancer therapies and the degree of reduction in serum le vels of prostaglandin E(2) and leukotriene B-4 by the agents in Lewis lung tumor bearing mice.