Inhibition of growth of primary and metastatic Lewis lung carcinoma cells by the phosphodiesterase inhibitor isobutylmethylxanthine.

Abstract Using a cloned line of Lewis lung carcinoma (LL1) cells adapted to cell culture, it has been demonstrated both in vitro and in vivo that noncytotoxic concentrations of the phosphodiesterase inhibitor isobutylmethylxanthine (IBX) are capable of inhibiting tumor colony formation. In vitro, the effect of 10-4m IBX is dependent upon the simultaneous presence of contact-inhibited C3H/10T½ mouse embryo fibroblast cells. The effects in vivo were studied in C57BL/6J mice by measuring the effects of IBX on lung nodule formation after i.v. injection of LL1 cells, on the growth of s.c. injected LL1 cells, on the growth of spontaneous metastases to the lungs, on body weight and on red and white blood cell counts. Administration of IBX as two daily injections beginning 2 days prior to i.v. tumor inoculation and continuing throughout the experiment resulted in a dose-dependent decrease (2- to 10-fold) in formation of lung nodules over a dose range of 5 to 20 mg/kg/injection. Administration of IBX (10 mg/kg/injection using the above protocol) to mice bearing a s.c. tumor resulted in 2- to 3-fold smaller primary tumors, an approximately 10-fold reduction in the number of lung metastases, smaller lung metastases, and the finding that only 4 of 24 treated versus 24 of 25 control mice had lung metastases. Treatment with IBX (10 mg/kg/injection) beginning 2 days after surgical removal of the primary tumor was equally effective in reducing lung metastases, and studies using 51Cr-labeled LL1 cells injected i.v. revealed no differences in initial arrest or subsequent release of LL1 cells from the lungs of treated or control mice. IBX (20 mg/kg/injection) given twice daily for 19 days caused no weight loss or change in red or white blood cell counts in treated versus control mice, and continuous exposure in vitro to 10-4m IBX caused no reduction in colony-forming ability of LL1 cells cultured in the absence of confluent C3H/10T½ cells. These findings, together with our previous studies in vitro, suggest that IBX causes a reduction in growth rate of malignant cells by enhancing the degree of interaction between growth-arrested normal cells and malignant cells, leading to the partial or complete growth arrest of the latter.