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

cells possess the ability to suppress the growth of cocultivated malignant cells and that this inhibition can be modulated by the concentration of serum (2) or by the presence of phosphodi esterase inhibitors such as IBX (3). In neither case could the phenomenon be attributed to the presence of diffusible growth inhibitory factors in the culture medium, but, in the case of IBX, this inhibition did correlate with its ability to elevate cyclic adenosine 3':5'-monophosphate levels in cells and in growth medium (3). Other investigators have also described the ability of cultured fibroblasts to inhibit the growth of malignant cells (12) and have shown that tumor promotors can suppress this inhibition (10). In vivo, little is known of the factors that control the growth rate of primary onmetastatic tumor cells, although it is apparent from studies on the latency of cancers in clinical (6) and experimental situations (7, 11) that tumor cells are not always free to proliferate in an autonomous manner. Indeed, the Ia tency of metastases and the low growth fraction of many human cancers are to a large extent responsible for the poor response rate of most chemotherapeutic regimens which are most effec tive against cycling cells. Because of these considerations and the need to validate our in vitro model in the in vivo situation, we have studied the growth rate of primary and metastatic Lewis lung carcinoma cells in mice treated with IBX, the most potent drug tested in vitro. The Lewis lung carcinoma was chosen for study because it has recently been adapted to cell culture in this laboratory (5), because it readily metastasizes to the lungs to produce discrete and readily counted foci, and because it is a tumor line which is well characterized (WI.