This study was undertaken in an attempt to understand the mechanism of antitumor action of
pyrimidinones alone and in combination with
cyclophosphamide (CY).
Pyrimidinones such as
2-amino-5-bromo-6-(3-fluorophenyl)-4(3H)pyrimidinone (
ABMFPP) were relatively nontoxic toward murine
L1210 leukemia cell growth in vitro with the concentration of
drug required for a 50% inhibition of cell growth being greater than 50 micrograms/ml. In contrast,
ABMFPP showed anti-B16
melanoma activity in vivo which was sensitive to X-irradiation of the hosts. These results collectively suggest that
pyrimidinones may act differently from conventional cytotoxic
antitumor agents. Multiple i.p.
injections of
ABMFPP (125 mg/kg/injection) significantly augmented the cytotoxicity of both natural killer cells and macrophages in peritoneal exudates. The augmentation of both effector cell populations was delayed, but was more pronounced when animals received a dose of CY (100 mg/kg) prior to
ABMFPP injections. The combination of CY and
ABMFPP also showed a synergistic anti-P388
leukemia effect which appeared to be related to the initial reduction of the
tumor burden by CY and the marked augmentation of the cytotoxicity of both natural killer cells and macrophages by
ABMFPP. The antitumor activity of
ABMFPP against
B16 melanoma was almost completely eliminated when animals received a dose of 400 rads X-irradiation 5 days prior to
tumor inoculation or a dose of 200 rads X-irradiation followed by several
injections of anti-asialo monosialoganglioside antibody. The administration of anti-asialo monosialoganglioside alone also markedly reduced the anti-B16
melanoma activity of
ABMFPP. The magnitude of reduction of the antitumor effect of
ABMFPP by radiation and/or anti-asialo monosialoganglioside antibody directly correlated with the inhibition of the
ABMFPP-mediated augmentation of immune responses. These results strongly suggest that the antitumor effect of
ABMFPP alone or in combination with CY is at least in part mediated through its augmentation of natural killer cell and/or macrophage activities.