Dipyridamole enhances an anti‐proliferative effect of interferon in various types of human tumor cells

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Abstract
The anti‐proliferative activity of human interferon (HulFN) was enhanced by dipyridamole, 2,6‐bis‐(diethanolamino)‐4,8‐dipiperidinopyrimido‐[5,4‐d]‐pyrimidine, when tested against various human tumor cell lines, including KT (breast carcinoma), PLC/PRF/5 (hepatoma), MGC‐1, U251‐SP and T98 (glioma), HAC‐2 and SHIN‐3 (ovarian carcinoma), and MM‐1CB (melanoma). The enhancement occurred irrespective of the kind of HulFN used (α, β or γ) and the original degree of susceptibility of the cells to HulFN. Even low doses down to 0.01 μM of dipyridamole that had no intrinsic anti‐proliferative activity could enhance the effect of HulFN. The enhancement of HulFN effects seems not to be caused by induction of HulFN production, because neither anti‐viral activity nor HulFN antigens were detected in culture medium in cells treated with dipyridamole. Mopidamole, a derivative of dipyridamole lacking one piperidine residue, produced little enhancement of the effects of HulFN. Among ovarian cancer cell lines tested, the enhancement of the activity of HulFN by dipyridamole for HAC‐2 and SHIN‐3 cells was equivalent to or greater than that for 3 chemotherapy agents (adriamycin, vincristine, and a camptothecin derivative). However, neither HOC‐21 ovarian cancer cells nor HEC‐1 endometrial adenocarcinoma cells were susceptible to any combinations. When MGC‐1, U251‐SP, and HAC‐2 cells were injected into nude mice, the growth of tumors was more markedly inhibited by the subcutaneous administration of HulFN in combination with oral administration of dipyridamole than by the HulFN alone. Thus, this combination therapy seems to be worth trying for human cancer, although the enhancement of the effects of HulFN by dipyridamole varied among the cell lines examined.