Azidothymidine and dipyridamole as biochemical response modifiers: synergism with methotrexate and 5-fluorouracil in human colon and pancreatic carcinoma cells

Abstract

Azidothymidine (AZT), inhibiting thymidine kinase (EC 2.7.1.21) (Weber, G. et al., Cancer Commun. 2:129-133, 1990) and dipyridamole, inhibiting nucleoside transport (Zhen, Y.-s. et al., Cancer Res. 43:1616-1619, 1983) exert blocking action on the activities of salvage pathways of nucleotide biosynthesis. Determined by clonogenic assay in human colon cancer HT-29 cells, the cell survivals for AZT, 10 microM, dipyridamole, 5 microM, and methotrexate (MTX), 0.025 microM, were 90, 82, and 62%, respectively; while the combinations of AZT + MTX, dipyridamole + MTX and AZT + dipyridamole + MTX, reduced survivals to 36, 4.3, and 0.7%. AZT or dipyridamole was synergistic with MTX, whereas AZT plus dipyridamole showed an even more marked potentiation of MTX activity. The survivals for 5-fluorouracil (5-FU), 0.5 microM, alone, AZT + 5-FU, dipyridamole + 5-FU, and AZT + dipyridamole + 5-FU were 86, 47, 29 and 5.1%, respectively. Similar results were observed in human pancreatic carcinoma BxPC-3 and PANC-1 cells. AZT markedly enhanced the inhibitory effect of dipyridamole in reversing the thymidine-hypoxanthine rescue from MTX cytotoxicity. AZT inhibited [14C]thymidine incorporation into DNA in HT-29 cells and strongly enhanced the effect of dipyridamole. The results indicate that combinations composed of AZT, dipyridamole, and antimetabolites, such as MTX and 5-FU, are potentially effective in the chemotherapy of human neoplasias.