bropirimine and Fibrosarcoma

In vivo and in vitro antitumor effects of an interferon (IFN)-alpha inducer, bropirimine (2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone), were examined in the murine tumor system. The antitumor effects were studied in Meth A cells, which were the most sensitive to bropirimine in the murine cell lines tested. The direct inhibitory activity of the drug was not reduced when Meth A cells were incubated with bropirimine and anti-IFNs, indicating that the inhibition is not due to autocrine IFN induction from tumor cells. The drug partially inhibited the uptake of [3H]thymidine, [3H]uridine and [3H]leucine. Cell cycle analysis with flow cytometry showed that the drug decreased G0/G1 phase and increased G2/M phase Meth A cells. The drug administered i.p. exhibited a remarkable antitumor effect against Meth A cells which were implanted i.p. These results suggested that the drug induced the in vivo antitumor effect by its direct antitumor activity.

Topics: Animals; Antineoplastic Agents; Cell Cycle; Cytosine; Drug Screening Assays, Antitumor; Fibrosarcoma; Humans; Interferon Inducers; Mice; Mice, Inbred BALB C; Rats; Tumor Cells, Cultured

Since pyrimidinone compounds induce interferon production in several animal species and have potent antivirus activities, it appeared important to determine whether these compounds could also induce antitumor activities in their recipients. Pyrimidinone compounds 2-amino-5-bromo-6-methyl-4-pyrimidinone (ABMP), 2-amino-5-brome-6-phenyl-4-pyrimidinone (ABPP), and 2-amino-5-iodo-6-phenyl-4-pyrimidinone (AIPP) were studied for their activities against artificial lung metastases of the weakly immunogenic spontaneous fibrosarcoma NFSa, the moderately immunogenic spontaneous mammary carcinoma MCa-K, and the strongly immunogenic 3-methylcholanthrene-induced fibrosarcoma FSa syngeneic to inbred C3Hf/Kam mice. In addition, the therapeutic efficacy of ABPP and AIPP was also determined against spontaneous lung metastases of NFSa. ABPP and AIPP given ip at 250 mg/kg for 2 or 3 consecutive days before or after iv inoculatin of NFSa, FSa, or MCa-K cells greatly reduced the number of tumor nodules developed in the lungs. ABMP, however, was considerably less effective. ABPP and AIPP were also effective in therapy of spontaneous lung metastases of NFSa, especially when these compounds were given before surgical removal of the primary tumor. Neither ABPP nor AIPP was effective against tumor nodules growing in whole-body irradiated (WBI) mice, but both protected mice against enhancement of lung metastasis formation induced by exposure to whole-body irradiation. ABPP was more effective than AIPP in inducing production of interferon in normal mice. When treated with ABPP, WBI mice, however, were unable to produce interferon. These results show that 6-phenyl-pyrimidinone compounds induce strong antitumor activities in mice, which correlated with neither tumor immunogenicity nor the ability of these agents to induce interferon, but which depended on the immune status of the tumor host.

Topics: Animals; Cytosine; Dose-Response Relationship, Drug; Fibrosarcoma; Immunity, Innate; Interferon Inducers; Interferons; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Pyrimidinones; Time Factors; Whole-Body Irradiation