Studies on the antitumor activities of pyrimidinone-interferon inducers. Part 2. Potentiation of antitumor resistance mechanisms.

In continuation of studies on antitumor activities of pyrimidinone interferon inducers, we report here that 2-amino-5-bromo-6-mF-phenyl-4(3H)-pyrimidinone (ABmFPP) is similarly effective to 2-amino-5-bromo-6-phenyl-4-pyrimidinone (ABPP) in its ability to reduce the number of metastatic nodules of a spontaneous fibrosarcoma (NFSa) and a spontaneous mammary carcinoma (MCa-K) in the lungs of C3Hf/Kam mice. Both compounds were more effective when given to mice prior to, rather than after, intravenous transplantation of tumor cells. In studies on the mechanism of the antitumor activity of pyrimidinones, 2-amino-5-iodo-6-phenyl-4-pyrimidinone (AIPP) was used in addition to ABPP and ABmFPP. These agents were capable of activating peritoneal macrophages that thus became capable of lysing in vitro 3T12 transformed cells but not syngeneic BALB/c embryo fibroblasts. Also, these agents were capable of augmenting significantly the natural killer (NK) cell activity in the spleen of C3Hf/Kam mice. Spleen cells from treated mice admixed to NFSa cells inhibited in vivo tumor take of these cells when the admixture was injected subcutaneously. Pyrimidinones were also effective against the development of NFSa nodules in the lungs of T-cell deficient mice implying that the presence of T-cells is not a prerequisite for the induction of antitumor activity by these agents. A further observation was that pyrimidinone compounds reduced the metastasis formation enhancing effect of cyclophosphamide. Therefore, pyrimidinone interferon inducers exhibit an appreciable antimetastatic activity mediated through antitumor resistance mechanisms involving activation of macrophages and stimulation of NK-cells.