MODULATION OF VINBLASTINE SENSITIVITY BY DIPYRIDAMOLE IN MULTIDRUG RESISTANT FIBROSARCOMA CELLS LACKING MDR1 EXPRESSION

We examined the ability of dipyridamole (DPM) to act synergistically with vinblastine (VBL) in HT1080 fibrosarcoma cells and a drug-resistant variant, HT1080/DR4, which lacks mdr1 expression, in order to determine whether DPM requires P-glycoprotein to modulate drug sensitivity. Median effect analysis of clonogenic assay was used to produce the combination index (CI50, values < 1 indicate synergy). DPM was mildly synergistic with VBL producing a CI50 of 0.83 +/- 0.13 for HT1080 cells and 0.80 +/- 0.16 for HT1080/DR4 cells. HT1080 and HT1080/DR4 cells accumulated 6.7 +/- 0.7 and 5.6 +/- 0.9 pmol H-3-VBL mg cells-1 at steady state (C(SS)) and 20-mu-M DPM elevated the C(SS) by 1.8 and 2.9-fold, respectively. In comparison, the CI50 was 1.1 +/- 0.2 in parental KB-3-1 cells and 0.1 +/- 0.1 in mdr1-expressing KB-GRCl cells. The KB-3-1 and KB-GRCl cells had a C(SS) of 3.8 +/- 0.8 and 0.7 +/- 0.2 pmol H-3-VBL mg cells-1, respectively, and DPM elevated the C(SS) by 9.2-fold in KB-GRCl cells. These studies demonstrate that DPM can produce synergy independently of mdrl expression but that much greater levels of synergy are achievable in mdr1-expressing tumour cells.