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 synthesi s, is an important target for cancer chemotherapy. Drugs that inhibit its individual components may act synergistically to block DNA synthes is. Prior work has established that gallium inhibits the R2 subunit of ribonucleotide reductase. We show that gallium acts synergistically w ith the ribonucleotide reductase inhibitors gemcitabine and hydroxyure a to inhibit the proliferation of CCRF-CEM cells. In contrast, combina tions of gallium with the ribonucleotide reductase inhibitors amidox, didox, or trimidox produced antagonistic effects on cell growth. Spect roscopy analysis revealed that as a result of their metal-binding prop erties, amidox, didox and trimidox formed complexes with gallium, thus negating potential synergistic actions. Our results have important im plications in the design of clinical trials using these ribonucleotide reductase inhibitors in combination. (C) 1998 Published by Elsevier S cience Ireland Ltd. All rights reserved.