Inhibition of 5-fluorouracil activation by oxipurinol in preparations of normal rat tissues and Jensen sarcoma: tumor-selective stimulation by inosine.
The effects of inosine on oxipurinol-induced inhibition of 5-fluorouracil (FUra) activation were investigated in a transplantable rat tumor and three normal rat tissues in vitro. FUra activation directed toward RNA was assessed in preparations of small intestine and Jensen sarcoma by determining the uptake of 14C-labeled FUra into purified total RNA of each tissue under identical conditions of incubation. Oxipurinol reduced the incorporation of FUra into intestinal RNA by as much as 93% but inhibited FUra uptake into tumor RNA by only about 45%. In the presence of sufficient oxipurinol to induce inhibition at approximately these levels, inosine failed to stimulate FUra uptake into intestinal RNA, whereas 0.1 mM inosine restored FUra uptake into Jensen sarcoma RNA to the level found in oxipurinol-free controls, and 0.5 mM inosine increased FUra uptake 29% above the controls. Both tissues had a nearly equivalent enzymatic capacity to cleave inosine by phosphorolysis. In view of what is currently known about the mechanism of action of oxipurinol and the metabolism of inosine, these results suggested that under our in vitro conditions rat small intestine was incapable of utilizing ribose-1-phosphate derived from inosine to stimulate the conversion of FUra to 5-fluorouridylate (FUMP), whereas Jensen sarcoma efficiently used this source of ribose-1-phosphate to increase the production of FUMP from FUra. In the absence of oxipurinol, inosine increased FUra uptake into total RNA of Jensen sarcoma by as much as 57%, compared to inosine-free controls, but markedly inhibited FUra uptake into total RNA of the small intestine.(ABSTRACT TRUNCATED AT 250 WORDS)
Beltz
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Department of Biochemistry, School of Medicine, Loma Linda University, California 92350.
Poland
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D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D001853:Bone Marrow / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism*; D066298:In Vitro Techniques; D007288:Inosine / Q000494:pharmacology*; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D010117:Oxypurinol / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012513:Sarcoma, Experimental / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism
D012334:RNA, Neoplasm; D007288:Inosine; D012313:RNA; D010117:Oxypurinol; D005472:Fluorouracil