Uridylate Trapping Induced by the C‐2‐Modified d‐Glucose Analogs Glucosone, Fluoroglucose, and Glucosamine

The interference of nucleotide metabolism induced by d‐arabino‐hexos‐2‐ulose (glucosone), 2‐deoxy‐2‐fluoro‐d‐glucose (fluoroglucose) and, for comparison, 2‐amino‐2‐deoxy‐d‐glucose (glucosamine) was studied in suspension cultures of TA3 mammary tumor cells. High‐performance liquid chromatography, [¹⁴C]uridine labeling and enzymatic analyses revealed that glucosone is metabolized to the UDP derivative leading to a diversion of [¹⁴C]uridylate from UTP into UDP‐glucosone. The accumulation of UDP‐glucosone, that was measured in TA3 as well as AS‐30D hepatoma cells, was associated with a depletion of UTP pools to less than 15% of control and a reduction of CTP contents to one third. UTP and CTP deficiency could be rapidly rcversed by addition of uridine to the cell suspension. Fluoroglucose acted both as a uridylate‐trapping and as a guanylate‐trapping hexose analog lowering the cellular contcnts of UTP and GTP to 5% and 27% of control, respectively. The lowering of GTP was accompanied by an increase in total acid‐soluble guanine nucleotides and a diversion of 84% of the [¹⁴C]guanylate into GDP‐fluoroglucose. As compared to fluoroglucose and glucosone, glucosamine was less effective in TA3 cells in decreasing the content of UTP. The uridylate‐trapping effect of glucosamine was in part compensated by the most active expansion of the acid‐soluble uridylate pool; this reflects an enhanced rate of dc novo pyrimidine synthesis that could be suppressed by the inhibitor 6‐azauridine. As a side effect probably resulting from phosphate trapping, glucosone, fluoroglucose, and glucosamine depressed the levels of ATP and of total adenine 5′‐nucleotides to a similar though moderate extent. The depletion of UTP, induced by these C‐2‐modified d‐glucose analogs, and additionally of GTP in the case of fluoroglucose, represent a metabolic lesion that may explain their growth inhibitory and cytotoxic effects.