SPECIFIC INHIBITORS DIRECTED AT THE INDIVIDUAL COMPONENTS OF RIBONUCLEOTIDE REDUCTASE AS AN APPROACH TO COMBINATION CHEMOTHERAPY

  • 1 January 1979
    • journal article
    • research article
    • Vol. 39  (11) , 4600-4604
Abstract
The ribonucleotide reductase from mouse tumors has been shown to consist of 2 nonidentical components (Tris and dye fractions, each prepared from the 20-40% (NH4)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 derivatives 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 [mouse ascites] 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. Combinations of inhibitors of ribonucleotide reductase which specifically inhibit the components may be useful in the treatment of cancer.

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