EFFECTS OF COMBINATIONS OF DRUGS HAVING DIFFERENT MODES OF ACTION AT THE RIBONUCLEOTIDE REDUCTASE SITE ON GROWTH OF L1210-CELLS IN CULTURE

  • 1 January 1982
    • journal article
    • research article
    • Vol. 42  (11) , 4353-4357
Abstract
Combinations of inhibitors directed at the individual components of ribonucleotide reductase were studied for their effects on L1210 cell [mouse leukemia] growth in culture. The combinations included pyrozoloimidazole (IMPY) plus deoxyadenosine and hydroxyurea plus deoxyadenosine. Modulators were utilized to potentiate the effects of hydroxyurea, IMPY or deoxyadenosine. Desferal was used to modulate the activity of hydroxyurea and IMPY while erythro-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 inhibition of L1210 cells at high drug concentrations, combinations 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 4-drug combination was clearly more effective than any 3-drug combination in terms of inhibition of tumor cell growth. The concentrations of the modulators (desferal or EHNA) were as critical as the concentrations of hydroxyurea, IMPY or deoxyadenosine in establishing an effective drug combination.