Effects of Combinations of Drugs Having Different Modes of Action at the Ribonucleotide Reductase Site on Growth of L1210 Cells in Culture1

Combinations of inhibitors directed at the individual compo nents of ribonucleotide reducÃ-asewere studied for their effects on L1210 cell growth in culture. The combinations included pyrozoloimidazole (IMPY) plus deoxyadenosine and hydroxyurea plus deoxyadenosine. Modulators were utilized to poten tiate the effects of hydroxyurea, IMPY, or deoxyadenosine. Desterai was used to modulate the activity of hydroxyurea and IMPY while erythoro-9-(2-hydroxy-3-nonyl)adenine (EHNA) was used as the modulator of deoxyadenosine metabolism. While the combinations of deoxyadenosine-EHNA, hydroxyurea-Desferal, or IMPY-Desferal caused increased growth in hibition of L1210 cells at high drug concentrations, combina tions which consisted of deoxyadenosine-EHNA-IMPY-Desferal or deoxyadenosine-EHNA-hydroxyurea-Desferal gave strong synergistic inhibition of L1210 cell growth in culture at concentrations of each of the drugs which alone had minimal inhibitory effects on tumor cell growth. The four-drug combi nation was clearly more effective than any three-drug combi nation in terms of inhibition of tumor cell growth. It was also observed that the concentrations of the modulators (Desterai or EHNA) were as critical as the concentrations of hydroxyurea, IMPY, or deoxyadenosine in establishing an effective drug combination.