Hormone, serum, and methylxanthine interactions in the regulation of DNA synthesis in organ-cultured rat mammary tumors.
Previous studies have shown that the growth of MTW9, a hormone-dependent rat mammary tumor, is stimulated by the presence of a mammosomatotropic tumor coimplant (MtTW10) but is inhibited by the administration of dibutyryl cyclic AMP (DBcAMP). This study examines the direct effect of serum taken from MtTW10-bearing WF rats (MtT serum) and of substances that increase cellular levels of cyclic AMP (cAMP) on DNA synthesis in organ-cultured MTW9. Explant DNA synthesis was significantly greater in the presence of MtT serum than in either normal female or male rat serum. Preparations of hormones known to be present in MtT serum failed to simulate the activity of MtT serum. Whereas 1 mM cAMP 1 mM did not alter DNA synthesis in MTW9 explants, inhibitors of cyclic nucleotide phosphodiesterases substantially suppressed the rate of [3H]thymidine incorporation into DNA. However, addition of MtT serum to cultures completely prevented the effects of these substances. This activity of MtT serum could not be duplicated by any of the following additions to the culture medium: normal female or male rat serum, National Institutes of Health (NIH) rat prolactin (2.5 micrograms/ml), NIH rat growth hormone (2.5 micrograms/ml), insulin (5 micrograms/ml), 17 beta-estradiol (5 micrograms/ml), or a hormone combination simulating the known endocrine constituents of MtT serum. The results suggested that the serum of the MtT-bearing animal contained an activity, unidentified at present, that could antagonize the growth-inhibitory action of the cAMP system and that may participate in the regulation of mammary tumor growth.