Specific inhibitors directed at the individual components of ribonucleotide reductase as an approach to combination chemotherapy.
It had been shown previously that the ribonucleotide reductase from mouse tumor consisted of two nonidentical components (Tris and dye fractions, each prepared from the 20 to 40% (NH/)2SO4 protein fraction containing the ribonucleotide reductase activity by blue dextran-Sepharose chromatography). The individual components either separated or present in the intact enzyme can be specifically and independently inhibited by different compounds. The Tris fraction component was inhibited by 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone while the dye fraction component was inactivated by pyridoxal phosphate:BH4- and the dialdehyde derivative of inosine (Inox) and 5'-deoxyinosine prepared by the periodate oxidation of inosine and 5'-deoxyinosine. The intact enzyme could be completely inhibited by any of these compounds. Reductase activity was restored by reconstitution with the exogenous components. The individual components of the reductase in the intact Ehrlich tumor cell could also be specifically inhibited. Activity in the crude cell-free extracts prepared from 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone- or Inox-treated cells was restored by the addition of the appropriate exogenous component. These data suggest that combinations of inhibitors of ribonucleotide reductase which specifically inhibit the components may be useful in the treatment of cancer.
D000447:Aldehydes / Q000008:administration & dosage; D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000201:enzymology; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D007288:Inosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D007546:Isoquinolines / Q000008:administration & dosage*; D051379:Mice; D011487:Protein Conformation; D011732:Pyridoxal Phosphate / Q000008:administration & dosage; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013882:Thiosemicarbazones / Q000008:administration & dosage*
D000447:Aldehydes; D007546:Isoquinolines; D013882:Thiosemicarbazones; C007390:inosine dialdehyde; C013118:4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone; D007288:Inosine; D011732:Pyridoxal Phosphate; D012264:Ribonucleotide Reductases