Regulation of GTP biosynthesis.
In the regulation of GTP biosynthesis, complex interactions are observed. A major factor is the behavior of the activity of IMPDH, the rate-limiting enzyme of de novo GTP biosynthesis, and the activity of GPRT, the salvage enzyme of guanylate production. The activities of GMP synthase, GMP kinase and nucleoside-diphosphate kinase are also relevant. In neoplastic transformation, the activities and amounts of all these biosynthetic enzymes are elevated as shown by kinetic assays and by immunotitration for IMPDH. In cancer cells, the up-regulation of guanylate biosynthesis is amplified by the concurrent decrease in activities of the catabolic enzymes, nucleotidase, nucleoside phosphorylase, and the rate-limiting purine catabolic enzyme, xanthine oxidase. The up-regulation of the capacity for GTP biosynthesis is also manifested in the stepped-up capacity of the overall pathways of de novo and salvage guanylate production. The linking with neoplasia is also seen in the elevation of the activities of IMPDH and GMP synthase and de novo and salvage pathways as the proliferative program is expressed as cancer cells enter log phase in tissue culture. The activity of GMP reductase showed no linkage with neoplastic or normal cell proliferation; however, in induced differentiation in HL-60 cells the activity increased concurrently with the decline in the activity of IMPDH. This reciprocal regulation of the two enzymes is observed in differentiation induced by retinoic acid, DMSO or TPA in HL-60 cells. In support of enzyme-pattern-targeted chemotherapy, evidence was provided for synergistic chemotherapy with tiazofurin (inhibitor of IMPDH) and hypoxanthine (competitive inhibitor of GPRT and guanine salvage activity) in patients and in tissue culture cell lines. These investigations should contribute to the clarification of the controlling factors of GMP biosynthesis, the role of the various enzymes, the behavior of GMP reductase in mammalian cells and the application of the approaches of enzyme-pattern-targeted chemotherapy in patients.
Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5200.
G
G
Weber
H
H
Nakamura
Y
Y
Natsumeda
T
T
Szekeres
M
M
Nagai
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D003110:Colonic Neoplasms / Q000188:drug therapy; D005069:Evaluation Studies as Topic; D050899:GMP Reductase; D006157:Guanosine Monophosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000097:blood / Q000627:therapeutic use; D007168:IMP Dehydrogenase / Q000378:metabolism; D007291:Inosine Monophosphate / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D012254:Ribavirin / Q000031:analogs & derivatives / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D007042:Hypoxanthines; D007291:Inosine Monophosphate; D019271:Hypoxanthine; D012254:Ribavirin; D006157:Guanosine Monophosphate; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; D009247:NADH, NADPH Oxidoreductases; D050899:GMP Reductase; C033706:tiazofurin