The effect of the nucleoside transport inhibitor dipyridamole on the incorporation of [3H]thymidine in the rat.
Dipyridamole is a non-specific inhibitor of nucleoside transport into mammalian cells. It is currently undergoing clinical evaluation in combination with various antimetabolites in an attempt to enhance the activity of these anticancer drugs by blocking the salvage of extracellular nucleosides, an important determinant of their cytotoxicity. In the present study, the effect of i.v. infusions of dipyridamole on [3H]thymidine incorporation into DNA has been examined in the anaesthetized rat. The tissues studied were bone marrow, gastrointestinal tract epithelium and the ascitic form of the Walker carcinosarcoma. Dipyridamole at 10 mg/kg, given over 3 hr, led to plasma levels of less than 5 microM and did not reduce [3H]thymidine incorporation into any of the tissues studied. At 40 mg/kg dipyridamole (plasma levels 10-15 microM) [3H]thymidine incorporation into the DNA of bone marrow and gastrointestinal tract epithelium was reduced to 20-30% of control values. Increasing the dose to 100 mg/kg did not lead to a further suppression of incorporation. Measurement of [3H]thymidine plasma pharmacokinetics and the intracellular distribution of tritium suggested that the inhibition of [3H]thymidine incorporation was due to reduced cellular uptake. In contrast to the effects on normal tissues, even at a lethal dose (200 mg/kg) dipyridamole did not significantly inhibit [3H]thymidine incorporation into Walker tumour cells. The levels of dipyridamole found in the ascitic fluid, at 100 mg/kg approximately half those in plasma, argue against a pharmacokinetic basis for this difference. Dipyridamole was found to bind extensively (97%) to rat plasma proteins, which may explain the discrepancy between the concentrations of dipyridamole required to inhibit nucleoside incorporation in vitro, in serum-free media, and those needed in vivo. From a comparison of the plasma levels of dipyridamole which cause an inhibition of [3H]thymidine incorporation in the rat with those which can be achieved safely in patients, it is concluded that dipyridamole is unlikely to markedly reduce nucleoside salvage in man.
D000818:Animals; D001665:Binding Sites; D001798:Blood Proteins / Q000378:metabolism; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D002279:Carcinoma 256, Walker / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis*; D004064:Digestive System / Q000187:drug effects / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology*; D005260:Female; D007262:Infusions, Intravenous; D007700:Kinetics; D009374:Neoplasms, Experimental; D051381:Rats; D011919:Rats, Inbred Strains; D013936:Thymidine / Q000097:blood / Q000378:metabolism*
D001798:Blood Proteins; D004176:Dipyridamole; D004247:DNA; D013936:Thymidine