Summary
Previous studies have shown that dipyridamole (DP), a potent nucleoside transport inhibitor blocking the rescue effect of exogenous nucleosides, markedly potentiates the cytotoxicity of antimetabolites. However, no enhancement of the chemotherapeutic effect of antimetabolites by DP in vivo has yet been reported. This study provided evidence that the combination of DP and amphotericin B (AmB) significantly potentiated the inhibitory effect of 5-fluorouracil (FU) or methotrexate (MTX) against a panel of transplantable tumors including sarcoma 180, cervical carcinoma U14, and Lewis lung carcinoma in mice. No significant increase in toxicity was induced by this combination in treated mice. Our results indicate that the combination of DP and AmB with antimetabolites is potentially useful in cancer chemotherapy.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Belt JA (1985) Potentiation of methotrexate in human lymphoblastoid cells by nitrobenzylthioinosine (NBMPR) and dipyridamole. Proc Am Assoc Cancer Res 26: 264
Cabral S, Leis S, Bover L, Nembrot M, Mordoh J (1984) Dipyridamole inhibits reversion by thymidine of methotrexate effect and increases drug uptake in sarcoma 180 cells. Proc Natl Acad Sci USA 81: 3200
Cadman EC, Dix DE, Handschumacher RE (1978) Clinical, biological, and biochemical effects of pyrazofurin. Cancer Res 38: 682
Chan TCK, Howell SB (1985) Mechanism of synergy between N-phosphonacetyl-1-aspartate and dipyridamole in a human ovarian carcinoma cell line. Cancer Res 45: 3598
Chan TCK, Young B, King ME, Taetle R, Howell SB (1985) Modulation of the activity of PALA by dipyridamole. Cancer Treat Rep 69: 425
Cheng YS, Li HT, Yang J (1965) A comparison of the destructive effects of five antitumor agents on various normal tissues in mice. Acta Pharm Sin 12: 606
Damon LE, Cadman EC (1986) Advances in rational combination chemotherapy. Cancer Invest 4: 421
Dustin P (1960) Die zytostatischen Substanzen und ihre Wirkung auf die Hämopoese. In: Heilmeyer L (ed) Handbuch der gesamten Hämatologie, vol 3, pt 1. Urban & Schwarzenberg, Munich, p 3
Fischer PH, Pamukcu R, Bittner G, Willson JKV (1984) Enhancement of the sensitivity of human colon cancer cells to growth inhibition by acivicin achieved through inhibition of nucleic acid precursor salvage by dipyridamole. Cancer Res 44: 3355
Grem JL, Fischer PH (1985) Augmentation of 5-fluorouracil cytotoxicity in human colon cancer cells by dipyridamole. Cancer Res 45: 2967
Kensler TW, Cooney DA (1981) Chemotherapeutic inhibitors of enzymes of the de novo pyrimidine pathway. Adv Pharmacol Chemother 18: 273
Mahony C, Wolfram KM, Cocchetto DM, Bjornsson TD (1982) Dipyridamole kinetics. Clin Pharm Ther 31: 330
Medoff G, Valeriote F, Dieckman J (1981) Potentiation of anticancer agents by amphotericin B. J Natl Cancer Inst 67: 131
Medoff J, Medoff G, Goldstein MN, Schlessinger D, Kobayashi GS (1975) Amphotericin B-induced sensitivity to actinomycin D in drug-resistant HeLa cells. Cancer Res 35: 2548
Muggia AL, Wagman E, Milles SS, Spiro HM (1963) Response of the gastrointestinal tract of the mouse to 5-fluorouracil. Am J Pathol 42: 407
Nelson JA, Drake S (1984) Potentiation of methotrexate toxicity by dipyridamole. Cancer Res 44: 2493
Newell DR, O'Connor PM, Calvert AH, Harrap KR (1986) The effect of the nucleoside transport inhibitor dipyridamole on the incorporation of [3H]thymidine in the rat. Biochem Pharmacol 35: 3871
Ozols RF, Hogan WM, Grotzinger KR, McCoy W, Young RC (1983) Effect of amphotericin B on Adriamycin and melphalan cytotoxicity in human and murine ovarian carcinoma and in L1210 leukemia. Cancer Res 43: 959
Presant CA, Carr D (1980) Amphotericin B (Fungizone) enhancement of nitrogen mustard uptake by human tumor cells. Biochem Biophys Res Commun 93: 1067
Presant CA, Hillinger S, Klahr C (1980) Phase II study of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, NSC//409962) with amphotericin B in bronchogenic carcinoma. Cancer 45: 6
Sobrero AF, Bertino JR (1985) Sequence-dependent synergism between dichloromethotrexate and cisplatin in a human colon carcinoma cell line. Cancer Treat Rep 69: 279
Valeriote F, Lynch R, Medoff G, Tolen S, Dieckman J (1978) Growth and rejection of leukemia cells in individual mice after combined treatment with amphotericin B and 1,3-bis(2-chloroethyl)-1-nitrosourea. J Natl Cancer Inst 61: 399
Valeriote F, Medoff G, Tolen S, Dieckman J (1984) Amphotericin B potentiation of the cytotoxicity of anticancer agents against both normal hematopoietic and leukemia cells in mice. J Natl Cancer Inst 73: 475
Weber G (1983) Biochemical strategy of cancer cells and the design of chemotherapy. Cancer Res 43: 3466
Weber G, Lui MS, Natsumeda Y, Faderan MA (1983) Salvage capacity of hepatoma 3924A and action of dipyridamole. Adv Enzyme Regul 21: 53
Weber G, Jayaram HN, Pillwein K, Natsumeda Y, Reardon MA, Zhen YS (1987) Salvage pathways as targets of chemotherapy. Adv Enzyme Regul 26: 335
Zhen YS, Lui MS, Weber G (1983) Effects of acivicin and dipyridamole on hepatoma 3924A cells. Cancer Res 43: 1616
Zhen YS, Reardon MA, Weber G (1986) Amphotericin B renders stationary phase hepatoma cells sensitive to dipyridamole. Biochem Biophys Res Commun 140: 434
Zhen YS, Reardon MA, Weber G (1987) Amphotericin B: a biological response modifier in targeting against the salvage pathways. Biochem Pharmacol 36: 3641
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Cao, Ss., Zhen, Ys. Potentiation of antimetabolite antitumor activity in vivo by dipyridamole and amphotericin B. Cancer Chemother. Pharmacol. 24, 181–186 (1989). https://doi.org/10.1007/BF00300240
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00300240