Dipyridamole Combined with Tumor Necrosis Factor‐α Enhances Inhibition of Proliferation in Human Tumor Cell Lines

In the search for cytokines whose antiproliferative action could be enhanced by combination with dipyridamole, 2,6‐bis(diethanolamino)‐4,8‐dipiperidinopyrimido[5,4,d]pyrimidine, the combination of tumor necrosis factor‐α (TNF‐α) with this agent was evaluated in various human tumor cell lines. Inhibition of the proliferation of human melanoma cell lines MM‐1CB and HMV‐1 by TNF‐α (1–10(2) U/ml) was enhanced in culture dishes by combination treatment with dipyridamole (0.1–10 μM). The enhancement effect was also detected in other tumor cell lines: T9S (glioma), SCC‐1CB (squamous cell carcinoma), HAC‐2 (ovarian clear‐cell carcinoma), HLE (hepatoma), HEC‐1 (endometrial adenocarcinoma) and HOC‐21 (ovarian serous cystadenocarcinoma). The incorporation of [(14)C]amino acids and [(3)H]nridine into acid‐insoluble cell materials in the combination‐treated cells was not significantly different from that in cells treated with TNF‐α or dipyridamole. However, the incorporation of [(3)H]thymidine was specifically inhibited in all cell lines examined after more than 12 h of the TNF‐α and dipyridamole combination treatment, although neither agent alone inhibited this incorporation. On the other band, the growth of tumors induced by the injection of MM‐1CB and HMV‐1 cells into nude mice was more markedly inhibited by the subcutaneous administration of TNF‐α in combination with orally administered dipyridamole than by either agent alone. The results presented suggested that dipyridamole is beneficial in assuring the effectiveness of anti‐cancer cytokine therapy.