Interaction of gallium nitrate with other inhibitors of ribonucleotide reductase: effects on the proliferation of human leukemic cells.
Ribonucleotide reductase, a key enzyme in deoxyribonucleotide synthesis, is an important target for cancer chemotherapy. Drugs that inhibit its individual components may act synergistically to block DNA synthesis. Prior work has established that gallium inhibits the R2 subunit of ribonucleotide reductase. We show that gallium acts synergistically with the ribonucleotide reductase inhibitors gemcitabine and hydroxyurea to inhibit the proliferation of CCRF-CEM cells. In contrast, combinations of gallium with the ribonucleotide reductase inhibitors amidox, didox, or trimidox produced antagonistic effects on cell growth. Spectroscopy analysis revealed that as a result of their metal-binding properties, amidox, didox and trimidox formed complexes with gallium, thus negating potential synergistic actions. Our results have important implications in the design of clinical trials using these ribonucleotide reductase inhibitors in combination.
Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee 53226, USA.
M S
MS
Myette
H L
HL
Elford
C R
CR
Chitambar
D000970:Antineoplastic Agents / Q000494:pharmacology; D001550:Benzamidines / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005708:Gallium / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D006918:Hydroxyurea / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
C074761:3,4,5-trihydroxybenzamidoxime; D000970:Antineoplastic Agents; D001550:Benzamidines; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D010091:Oximes; D003841:Deoxycytidine; C070491:Amidox; D005708:Gallium; D012264:Ribonucleotide Reductases; C035419:3,4-dihydroxybenzohydroxamic acid; C027235:gallium nitrate; D006918:Hydroxyurea; D000093542:Gemcitabine