Modulation of cytarabine metabolism in the human promyelocytic leukemia cell line HL-60 by polyhydroxy-substituted benzohydroxamic acids.
Two potent new ribonucleotide reductase inhibitors, 3,4,5-trihydroxybenzohydroxamic acid (VF 122) and 3,4-dihydroxybenzohydroxamic acid (VF 147), were investigated for their ability to modulate the cellular pharmacology of cytarabine (ara-C) in HL-60 cells. VF 122 and VF 147 increased the total cellular uptake of ara-C by a mean (+/- SE) of 8% +/- 3% and 29% +/- 3%, respectively, when measured 2 hours after the start of exposure to 0.1 microM ara-C. This effect was evident after only 10 minutes of exposure to the riboNucleotide reductase inhibitor and did not vary significantly over the concentration range of 10-100 microM for either agent. VF 122 enhanced the incorporation of ara-CTP into DNA by 3.6-fold; VF 147 produced a 5.6-fold increase. In comparison, the maximum enhancement achievable with hydroxyurea was 2.1-fold, and with thymidine was 1.8-fold. These results provide a biochemical rationale for further investigation of these agents in combination with ara-C.
D002460:Cell Line; D003561:Cytarabine / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000378:metabolism*; D013997:Time Factors
D006877:Hydroxamic Acids; D003561:Cytarabine; C036110:3,4,5-trihydroxybenzohydroxamic acid; D004247:DNA; C035419:3,4-dihydroxybenzohydroxamic acid