Biochemically directed therapy of leukemia with tiazofurin, a selective blocker of inosine 5'-phosphate dehydrogenase activity.
Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), a selective inhibitor of the activity of IMP dehydrogenase (EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, provided in end stage leukemic patients a rapid decrease of IMP dehydrogenase activity and GTP concentration in the blast cells and a subsequent decline in blast cell count. Sixteen consecutive patients with end stage acute nonlymphocytic leukemia or myeloid blast crisis of chronic granulocytic leukemia were treated with tiazofurin. Allopurinol was also given to inhibit xanthine oxidase activity to decrease uric acid excretion and to elevate the serum concentration of hypoxanthine, which should competitively inhibit the activity of hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8), the salvage enzyme of guanylate synthesis. Assays of IMP dehydrogenase activity and GTP concentration in leukemic cells provided a method to monitor the impact of tiazofurin and allopurinol and to adjust the drug doses. In this group of patients with poor prognosis, five attained a complete hematological remission and one showed a hematological improvement. A marked antileukemic effect was seen in two other patients. All five evaluable patients with myeloid blast crisis of chronic granulocytic leukemia reentered the chronic phase of their disease. Five patients with acute nonlymphocytic leukemia were refractory to tiazofurin and three were unevaluable for hematological effect because of early severe complications. Responses with intermittent 5- to 15-day courses of tiazofurin lasted 3-10 months. Tiazofurin had a clear antiproliferative effect, but the pattern of hematological response indicated that it appeared to induce differentiation of leukemic cells. In spite of toxicity with severe or life-threatening complications in 11 of 16 patients, tiazofurin was better tolerated in most patients than other antileukemic treatment modalities and provided a rational, biochemically targeted, and biochemically monitored chemotherapy which should be of interest in the treatment of leukemias and as a paradigm in enzyme pattern-targeted chemotherapy.
Tricot
G J
GJ
Department of Medicine, Indiana University School of Medicine, Indianapolis 46223.
Jayaram
H N
HN
Lapis
E
E
Natsumeda
Y
Y
Nichols
C R
CR
Kneebone
P
P
Heerema
N
N
Weber
G
G
Hoffman
R
R
D000964:Antimetabolites, Antineoplastic; D001752:Blast Crisis; D001772:Blood Cell Count / Q000187:drug effects; D001853:Bone Marrow / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007658:Ketone Oxidoreductases / Q000037:antagonists & inhibitors*; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D012254:Ribavirin / Q000031:analogs & derivatives / Q000627:therapeutic use*; D012263:Ribonucleosides / Q000627:therapeutic use*
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D012263:Ribonucleosides; D012254:Ribavirin; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; D007658:Ketone Oxidoreductases; C033706:tiazofurin