Modulation of 5-fluorouracil and 5-fluorouridine toxicity by membrane transport inhibitors in normal tissues of rats with liver adenocarcinoma.
The cytotoxicity of 5-FU and 5-FUrd, given via the hepatic artery, was measured by its incorpotation into the acid soluble fraction, RNA and DNA in normal tissues and an adenocarcinoma transplanted into the liver in rats. Drugs inhibiting the membrane transport of, especially, nucleosides were simultaneously administered by a femoral vein to modulate the cytotoxicity. None of them (dipyridamole, lidoflazine nor dilazep) had any statistically significant influence on the tumour. Dipyridamole and lidoflazine decreased the incorporation of 5-FU into the acid soluble fraction, RNA and DNA of the intestine. Dipyridamole probably decreased the incorporation of 5-FUrd into the acid soluble fraction and RNA of the intestine. Lidoflazine has not been tested with 5-FUrd. Dipyridamole increased the incorporation of 5-FU into the acid soluble fraction of liver, bone marrow and kidney, and of 5-FUrd into the acid soluble fraction of liver and bone marrow and liver RNA. Lidoflazine had fewer adverse effects. Both dipyridamole and lidoflazine increased the combined peak of UTP and FUTP in the liver, and dipyridamole also in the intestine of 5-FU treated rats. Dipyridamole which undergoes an enterohepatic circulation increased the combined peak of UDP-glucuronic acid and FUDP-glucuronic acid in 5-FU and 5-FUrd treated rats, as well as UDP-glucuronic acid in rats given neither 5-FU nor 5-FUrd in the liver. Membrane transport inhibitors seem to offer the opportunity to protect normal tissues from the cytotoxicity of 5-fluoropyrimidines, but the tissues can also be more exposed.