Antineoplastic properties of pyrimidinone interferon inducers

Abstract

The interferon inducing, antiviral and antitumor activities of a new series of pyrimidinone compounds are compared and summarized in this report. An interesting split in mechanism of action appeared to exist in these compounds. One group represented by ABPP were very potent interferon inducing agents and the antiviral and antitumor activity of these agents correlated with their ability to induce interferon. The second group as exemplified by AIPP were not good inducers yet were just as active against virus infection and neoplastic disease. Presumably the split in antiviral and antitumor activity of these molecules was mediated by other host defense mechanisms as indicated by their ability to modulate various immune functions. Additional evidence for this has been reported by H. E. Renis et al. (24). They found that treatment of mice with antithymocyte serum along with AIPP or ABMP blocked the antiherpes simplex virus activity of the molecules. That is, that mice treated with AIPP or ABPP were effectively protected against virus infection but if a single dose of antithymocyte serum was given along with drug, the ability of the molecules to protect against virus infection was inhibited. These results suggest that the thymocyte played a critical role in mediating anti-Herpes virus and possible antitumor activity. This concept is further enhanced by the fact that each of the pyrimidinones did not have antiviral activity in vitro in various fibroblast cell culture monolayers. The antitumor activity of the pyrimidinones was very dependent upon tumor load. If too high a tumor load was injected, the animals were not protected against the lethal consequences of the neoplastic disease. We have reported similar observations with these compounds in mice where the antiviral activity of the molecules was overcome by increasing the level of virus injected (25). These observations suggest that the most efficient use of such molecules might be in combination chemotherapy with conventional cytotoxic or antiviral agents. Some clue as to why this is the case is given by studies in which mice were injected with malignant melanoma cells and the metastatic rate was monitored. In these studies the number of metastatic nodules in each mouse could be reduced but the number of mice without metastatic nodules was not significantly decreased indicating that the molecules could decrease the tumor load but not completely rid the animal of neoplastic cells. Although we presently do not know if interferon or interferon inducers will be effective in humans for the treatment of virus infections or neoplastic disease, ongoing studies should help answer these questions. The pyrimidinones are presently in preliminary clinical trials aimed at determining if they will induce interferon in humans and what effect they will have on various immune parameters. Results from these studies should provide answers as to the potential benefit of this interesting group of compounds.