Reference

Evidence that intracellular synthesis of 5-fluorouridine 5'-phosphate from 5-fluorouracil and 5-fluorouridine is compartmentalized

Evidence that intracellular synthesis of 5-fluorouridine 5'-phosphate from 5-fluorouracil and 5-fluorouridine is compartmentalized. Shani, Jashovam; Danenberg, Peter V. (Sch. Med., Univ. South. California, Los Angeles, CA 90033, USA). Biochem. Biophys. Res. Commun., 122(1), 439-45 (English) 1984. CODEN: BBRCA9. ISSN: 0006-291X. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) L1210 cells were exposed to equitoxic concns. of 14C-labeled 5-fluorouracil [51-21-8] and 3H-labeled 5-fluorouridine [316-46-1] for 4 h. The RNA from these cells was sepd. into cytosolic and nuclear fractions, and then further fractionated by chromatog. on poly-U Sepharose, Sephadex G-200, and DEAE-cellulose. The ratio of 3H to 14C incorporated into various species of RNA differed by as much as 6-fold, indicating that the resp. 5-fluorouridine 5'-monophosphates synthesized from the 2 precursors are localized in sep. pools that do not mix rapidly.

Effect of uridine on response of 5-azacytidine-resistant human leukemic cells to inhibitors of de novo pyrimidine synthesis

Effect of uridine on response of 5-azacytidine-resistant human leukemic cells to inhibitors of de novo pyrimidine synthesis. Grant, S.; Bhalla, K.; Gleyzer, M. (Coll. Physicians Surg., Columbia Univ., New York, NY 10032, USA). Cancer Res., 44(12, Pt. 1), 5505-10 (English) 1984. CODEN: CNREA8. ISSN: 0008-5472. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) A uridine-cytidine kinase [9026-39-5]-deficient human promyelocytic leukemic subline (HL-60-5-aza-Cyd), which is highly resistant to the antileukemic agent 5-azacytidine (I) [320-67-2], was isolated. Resistant cells exposed to 10-5M 5-azacytidine for 2 h exhibited a marked redn. in both the total intracellular accumulation of 5-azacytidine (11.9 vs. 156.0 pmol/106 cells) as well as its incorporation into RNA (3.1 vs. 43.4 pmol/mg D-ribose) compared to the parent line. These biochem. changes were assocd. with nearly a 100-fold decrease in sensitivity to the growth inhibitory effects of 5-azacytidine (concn. of drug assocd. with a 5% redn. in cell growth, 3.5 ′ 10-5 vs. 5.0 ′ 10-7M). 5-Azacytidine-resistant cells exhibited cross-resistance to 3-deazauridine [23205-42-7], 6-azauridine [54-25-1], and 5-fluorouridine [316-46-1], but not to 1-b-D-arabinofuranosylcytosine [147-94-4], 2'-deoxyazacytidine [2353-33-5], or 5-aza-1-b-D-arabinofuranosylcytosine [65886-71-7]. Coadministration of 50 mM uridine [58-96-8] prevented depletion of pyrimidine nucleoside triphosphates and inhibition of colony formation of HL-60 cells exposed to 3 mM N-(phosphonacetyl)-L-aspartate) [51321-79-0] or 5 ′ 10-6M pyrazofurin [30868-30-5] but was not capable of protecting HL-60-5-azacytidine under the same conditions. This uridine concn. was also able to restore control colony formation to normal human bone marrow progenitor cells (granulocyte-macrophage colony-forming units) exposed to de novo pyrimidine biosynthetic blockade. These in vitro studies suggest that 5-azacytidine resistant cells lacking the pyrimidine salvage pathway enzyme uridine-cytidine kinase may be selectively vulnerable to a regimen using pyrimidine antagonists administered in conjunction with the naturally occurring nucleoside uridine.