RESISTANCE TO THE ANTITUMOR AGENT GALLIUM NITRATE IN HUMAN LEUKEMIC-CELLS IS ASSOCIATED WITH DECREASED GALLIUM IRON UPTAKE, INCREASED ACTIVITY OF IRON REGULATORY PROTEIN-1, AND DECREASED FERRITIN PRODUCTION/

The mechanism of drug resistance to gallium nitrate is not known. Sinc e gallium can be incorporated into ferritin, an iron storage protein t hat protects cells from iron toxicity, we investigated whether ferriti n expression was altered in gallium-resistant (R) CCRF-CEM cells. We f ound that the ferritin content of R cells was decreased, while heavy c hain ferritin mRNA levels and iron regulatory protein-1 (IRP-1) RNA bi nding activity were increased. IRP-1 protein levels were similar in ga llium-sensitive (S) and R cells, indicating that R cells contain a gre ater proportion of IRP-1 in a high affinity mRNA binding state. Fe-59 uptake and transferrin receptor expression were decreased in R cells. In both S and R cells, gallium inhibited cellular Fe-59 uptake, increa sed ferritin mRNA and protein, and decreased IRP-1 binding activity. G allium uptake by R cells was markedly diminished; however, the sensiti vity of R cells to gallium could be restored by increasing their uptak e of gallium with excess transferrin. Our results suggest that R cells have developed resistance to gallium by down-regulating their uptake of gallium. In parallel, iron uptake by R cells is also decreased, lea ding to changes in iron homeostasis. Furthermore, since gallium has di vergent effects on iron uptake and ferritin synthesis, its action may also include a direct effect on ferritin mRNA induction and IRP-1 acti vity.