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 less than 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 3H-VBL mg cells-1 at steady state (Css) and 20 microM DPM elevated the Css 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-GRC1 cells. The KB-3-1 and KB-GRC1 cells had a Css of 3.8 +/- 0.8 and 0.7 +/- 0.2 pmol 3H-VBL mg cells-1, respectively, and DPM elevated the Css by 9.2-fold in KB-GRC1 cells. These studies demonstrate that DPM can produce synergy independently of mdr1 expression but that much greater levels of synergy are achievable in mdr1-expressing tumour cells.
Department of Medicine, University of California, San Diego, La Jolla 92093-0812.
D R
DR
Shalinsky
M L
ML
Slovak
S B
SB
Howell
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004176:Dipyridamole / Q000494:pharmacology*; D004351:Drug Resistance; D004357:Drug Synergism; D005354:Fibrosarcoma / Q000737:chemistry / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008562:Membrane Glycoproteins / Q000032:analysis; D009363:Neoplasm Proteins / Q000032:analysis; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D014747:Vinblastine / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D014747:Vinblastine; D004176:Dipyridamole