Effects of biochemical modulation of drug combinations directed at the ribonucleotide reductase site on leukemia L1210 cell growth in culture.
Ribonucleotide reductase from tumor cells consists of two non-identical components which can be specifically and independently inhibited. Combinations of agents directed at the individual components gave synergistic inhibition of L1210 cell growth in culture. Utilizing hydroxyurea and deoxyadenosine or IMPY and deoxyadenosine as the parent combinations, modulators were used to potentiate the effects of each of these drugs. EHNA was used to prevent the deamination of deoxyadenosine while Desferal was utilized to increase the effects of hydroxyurea and IMPY. Combinations consisting of deoxyadenosine/EHNA plus IMPY/Desferal and deoxyadenosine/EHNA plus hydroxyurea/Desferal gave synergistic inhibition of L1210 cell growth. Utilizing these combination chemotherapies, the concentrations of each of the agents could be kept to minimal, essentially non-inhibitory levels and yet still achieve complete inhibition of L1210 cell growth with the specifically generated four-drug combinations.
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D003839:Deoxyadenosines / Q000494:pharmacology; D004357:Drug Synergism; D006918:Hydroxyurea / Q000494:pharmacology; D007939:Leukemia L1210 / Q000201:enzymology*; D011720:Pyrazoles / Q000494:pharmacology; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*
D003839:Deoxyadenosines; D011720:Pyrazoles; C010192:9-(2-hydroxy-3-nonyl)adenine; D012264:Ribonucleotide Reductases; D003676:Deferoxamine; D000225:Adenine; C000971:2,3-dihydro-1H-imidazo(1,2-b)pyrazole; D006918:Hydroxyurea