Biochemically Directed Therapy of Leukemia with Tiazofurin, a Selective Blocker of Inosine 5′-Phosphate Dehydrogenase Activity

Guido J. Tricot, Craig R. Nichols, Pat Kneebone, Ronald Hoffman, Hiremagalur N. Jayaram, Elizabeth Lapis, Yutaka Natsumeda, George Weber, Nyla Heerema

Research output: Contribution to journalArticle

136 Citations (Scopus)

Abstract

Tiazofurin (2-β-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.

Original languageEnglish (US)
Pages (from-to)3696-3701
Number of pages6
JournalCancer Research
Volume49
Issue number13
StatePublished - Jul 1 1989

Fingerprint

tiazofurin
Inosine Nucleotides
Oxidoreductases
Leukemia
IMP Dehydrogenase
Guanosine Triphosphate
Blast Crisis
Allopurinol
Therapeutics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Acute Myeloid Leukemia
Enzymes
Hypoxanthine Phosphoribosyltransferase
Drug Therapy
Hypoxanthine
Xanthine Oxidase
Uric Acid

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tricot, G. J., Nichols, C. R., Kneebone, P., Hoffman, R., Jayaram, H. N., Lapis, E., ... Heerema, N. (1989). Biochemically Directed Therapy of Leukemia with Tiazofurin, a Selective Blocker of Inosine 5′-Phosphate Dehydrogenase Activity. Cancer Research, 49(13), 3696-3701.

Biochemically Directed Therapy of Leukemia with Tiazofurin, a Selective Blocker of Inosine 5′-Phosphate Dehydrogenase Activity. / Tricot, Guido J.; Nichols, Craig R.; Kneebone, Pat; Hoffman, Ronald; Jayaram, Hiremagalur N.; Lapis, Elizabeth; Natsumeda, Yutaka; Weber, George; Heerema, Nyla.

In: Cancer Research, Vol. 49, No. 13, 01.07.1989, p. 3696-3701.

Research output: Contribution to journalArticle

Tricot, GJ, Nichols, CR, Kneebone, P, Hoffman, R, Jayaram, HN, Lapis, E, Natsumeda, Y, Weber, G & Heerema, N 1989, 'Biochemically Directed Therapy of Leukemia with Tiazofurin, a Selective Blocker of Inosine 5′-Phosphate Dehydrogenase Activity', Cancer Research, vol. 49, no. 13, pp. 3696-3701.
Tricot GJ, Nichols CR, Kneebone P, Hoffman R, Jayaram HN, Lapis E et al. Biochemically Directed Therapy of Leukemia with Tiazofurin, a Selective Blocker of Inosine 5′-Phosphate Dehydrogenase Activity. Cancer Research. 1989 Jul 1;49(13):3696-3701.
Tricot, Guido J. ; Nichols, Craig R. ; Kneebone, Pat ; Hoffman, Ronald ; Jayaram, Hiremagalur N. ; Lapis, Elizabeth ; Natsumeda, Yutaka ; Weber, George ; Heerema, Nyla. / Biochemically Directed Therapy of Leukemia with Tiazofurin, a Selective Blocker of Inosine 5′-Phosphate Dehydrogenase Activity. In: Cancer Research. 1989 ; Vol. 49, No. 13. pp. 3696-3701.
@article{024596ff077b4172ab68b2508bd87ec2,
title = "Biochemically Directed Therapy of Leukemia with Tiazofurin, a Selective Blocker of Inosine 5′-Phosphate Dehydrogenase Activity",
abstract = "Tiazofurin (2-β-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.",
author = "Tricot, {Guido J.} and Nichols, {Craig R.} and Pat Kneebone and Ronald Hoffman and Jayaram, {Hiremagalur N.} and Elizabeth Lapis and Yutaka Natsumeda and George Weber and Nyla Heerema",
year = "1989",
month = "7",
day = "1",
language = "English (US)",
volume = "49",
pages = "3696--3701",
journal = "Cancer Research",
issn = "0008-5472",
number = "13",

}

TY - JOUR

T1 - Biochemically Directed Therapy of Leukemia with Tiazofurin, a Selective Blocker of Inosine 5′-Phosphate Dehydrogenase Activity

AU - Tricot, Guido J.

AU - Nichols, Craig R.

AU - Kneebone, Pat

AU - Hoffman, Ronald

AU - Jayaram, Hiremagalur N.

AU - Lapis, Elizabeth

AU - Natsumeda, Yutaka

AU - Weber, George

AU - Heerema, Nyla

PY - 1989/7/1

Y1 - 1989/7/1

N2 - Tiazofurin (2-β-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.

AB - Tiazofurin (2-β-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.

UR - http://www.scopus.com/inward/record.url?scp=0024394730&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0024394730&partnerID=8YFLogxK

M3 - Article

C2 - 2567208

AN - SCOPUS:0024394730

VL - 49

SP - 3696

EP - 3701

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 13

ER -