Pharmacologic basis for the use of dipyridamole to increase the selectivity of intraperitoneally delivered methotrexate.
Dipyridamole (DP) is an attractive agent with which to increase the selectivity of intraperitoneally delivered methotrexate (MTX). We demonstrated that DP synergistically increased the cytotoxicity of MTX to the human OV 2008 ovarian carcinoma cell line in vitro and that this synergy was highly concentration-dependent. DP did not alter MTX binding in plasma, and vice versa. We found that the two drugs were chemically compatible at concentrations of less than 400 microM, which was well above the concentration needed to make continuous i.p. infusion feasible. The ability of OV 2008 cells to accumulate uridine was used as a bioassay for the in vivo activity of DP. When this drug was infused i.p. at 12 mg/m2 per day, the steady-state peritoneal DP concentrations attained in patients were sufficient for maximal inhibition of uridine uptake, indicating concentrations high enough for synergism with MTX. We found no correlation between total peritoneal protein concentration and either free DP concentration or biologic activity. On the basis of these preclinical and pharmacologic measurements, we conclude that it should be possible to produce selective i.p. biochemical modulation of MTX with DP.
Goel
R
R
Department of Medicine, University of California, San Diego, La Jolla 92093.
Sanga
R
R
Howell
S B
SB
D001202:Ascitic Fluid / Q000032:analysis / Q000378:metabolism; D002460:Cell Line / Q000187:drug effects; D004176:Dipyridamole / Q000008:administration & dosage / Q000032:analysis / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D008727:Methotrexate / Q000008:administration & dosage* / Q000097:blood; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D004176:Dipyridamole; D008727:Methotrexate