Phase I trial and biochemical evaluation of tiazofurin administered on a weekly schedule

T. J. Melink, G. Sarosy, A. R. Hanauske, J. L. Phillips, J. H. Bayne, M. R. Grever, H. N. Jayaram, D. D. Von Hoff

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Tiazofurin (2-B-D-ribofuranosylthiazole-4-Carboxamide: NSC 286193) is a nucleoside antimetabolite that acts as a potent inhibitor of IMP dehydrogenase resulting in a guanine nucleotide deprivation. Recent in vivo biochemical observations in rats bearing hepatoma suggested a correlation between depletion of guanine nuncleotides and antitumor effect. The present phase I trial utilized a weekly x 3 bolus infusion schedule, repeated every 5 weeks. Biochemical measurement of GTP and dGTP were performed in patients at each dose level. Twelve patients received 16 courses of the drug in doses ranging from 1100 to 2050 mg/m2 weekly x 3. The dose limiting toxicities were pericarditis and clinical symptoms suggestive of a more generalized serositis (chests and abdominal pain). Other toxicities included reversible elevations in CPK (MM band only) and SGOT, nausea, vomiting, and arthralgias. Neurotoxic effects were generally mild, including headaches, anxiety, and malaise. Only 1 of 6 patients evaluated for tiazofurin's biochemical activity showed a sustained depletion of guanine nucleotide pools. No antitumor activity was observed. The maximally tolerated dose of tiazofurin on this intermittent weekly x 3 schedule was 1650 mg/m2. Toxicity and the overall lack of biochemical and biologic effect at clinically achievable doses may preclude further clinical evaluation of this drug on weekly schedule. The toxicities observed in our study were similar to those reported for phase I investigations using a considerably higher dose intensity with daily x 5 schedules.

Original languageEnglish (US)
Pages (from-to)51-61
Number of pages11
JournalSelective Cancer Therapeutics
Volume6
Issue number1
StatePublished - 1990
Externally publishedYes

Fingerprint

tiazofurin
Appointments and Schedules
Guanine Nucleotides
IMP Dehydrogenase
Serositis
Antimetabolites
Drug Evaluation
Pericarditis
Maximum Tolerated Dose
Arthralgia
Guanine
Aspartate Aminotransferases
Guanosine Triphosphate
Chest Pain
Nucleosides
Nausea
Abdominal Pain
Vomiting
Headache
Hepatocellular Carcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology

Cite this

Melink, T. J., Sarosy, G., Hanauske, A. R., Phillips, J. L., Bayne, J. H., Grever, M. R., ... Von Hoff, D. D. (1990). Phase I trial and biochemical evaluation of tiazofurin administered on a weekly schedule. Selective Cancer Therapeutics, 6(1), 51-61.

Phase I trial and biochemical evaluation of tiazofurin administered on a weekly schedule. / Melink, T. J.; Sarosy, G.; Hanauske, A. R.; Phillips, J. L.; Bayne, J. H.; Grever, M. R.; Jayaram, H. N.; Von Hoff, D. D.

In: Selective Cancer Therapeutics, Vol. 6, No. 1, 1990, p. 51-61.

Research output: Contribution to journalArticle

Melink, TJ, Sarosy, G, Hanauske, AR, Phillips, JL, Bayne, JH, Grever, MR, Jayaram, HN & Von Hoff, DD 1990, 'Phase I trial and biochemical evaluation of tiazofurin administered on a weekly schedule', Selective Cancer Therapeutics, vol. 6, no. 1, pp. 51-61.
Melink TJ, Sarosy G, Hanauske AR, Phillips JL, Bayne JH, Grever MR et al. Phase I trial and biochemical evaluation of tiazofurin administered on a weekly schedule. Selective Cancer Therapeutics. 1990;6(1):51-61.
Melink, T. J. ; Sarosy, G. ; Hanauske, A. R. ; Phillips, J. L. ; Bayne, J. H. ; Grever, M. R. ; Jayaram, H. N. ; Von Hoff, D. D. / Phase I trial and biochemical evaluation of tiazofurin administered on a weekly schedule. In: Selective Cancer Therapeutics. 1990 ; Vol. 6, No. 1. pp. 51-61.
@article{563a9eab2b434424bc50fe7780d0ca22,
title = "Phase I trial and biochemical evaluation of tiazofurin administered on a weekly schedule",
abstract = "Tiazofurin (2-B-D-ribofuranosylthiazole-4-Carboxamide: NSC 286193) is a nucleoside antimetabolite that acts as a potent inhibitor of IMP dehydrogenase resulting in a guanine nucleotide deprivation. Recent in vivo biochemical observations in rats bearing hepatoma suggested a correlation between depletion of guanine nuncleotides and antitumor effect. The present phase I trial utilized a weekly x 3 bolus infusion schedule, repeated every 5 weeks. Biochemical measurement of GTP and dGTP were performed in patients at each dose level. Twelve patients received 16 courses of the drug in doses ranging from 1100 to 2050 mg/m2 weekly x 3. The dose limiting toxicities were pericarditis and clinical symptoms suggestive of a more generalized serositis (chests and abdominal pain). Other toxicities included reversible elevations in CPK (MM band only) and SGOT, nausea, vomiting, and arthralgias. Neurotoxic effects were generally mild, including headaches, anxiety, and malaise. Only 1 of 6 patients evaluated for tiazofurin's biochemical activity showed a sustained depletion of guanine nucleotide pools. No antitumor activity was observed. The maximally tolerated dose of tiazofurin on this intermittent weekly x 3 schedule was 1650 mg/m2. Toxicity and the overall lack of biochemical and biologic effect at clinically achievable doses may preclude further clinical evaluation of this drug on weekly schedule. The toxicities observed in our study were similar to those reported for phase I investigations using a considerably higher dose intensity with daily x 5 schedules.",
author = "Melink, {T. J.} and G. Sarosy and Hanauske, {A. R.} and Phillips, {J. L.} and Bayne, {J. H.} and Grever, {M. R.} and Jayaram, {H. N.} and {Von Hoff}, {D. D.}",
year = "1990",
language = "English (US)",
volume = "6",
pages = "51--61",
journal = "Selective Cancer Therapeutics",
issn = "1043-0733",
publisher = "Mary Ann Liebert Inc.",
number = "1",

}

TY - JOUR

T1 - Phase I trial and biochemical evaluation of tiazofurin administered on a weekly schedule

AU - Melink, T. J.

AU - Sarosy, G.

AU - Hanauske, A. R.

AU - Phillips, J. L.

AU - Bayne, J. H.

AU - Grever, M. R.

AU - Jayaram, H. N.

AU - Von Hoff, D. D.

PY - 1990

Y1 - 1990

N2 - Tiazofurin (2-B-D-ribofuranosylthiazole-4-Carboxamide: NSC 286193) is a nucleoside antimetabolite that acts as a potent inhibitor of IMP dehydrogenase resulting in a guanine nucleotide deprivation. Recent in vivo biochemical observations in rats bearing hepatoma suggested a correlation between depletion of guanine nuncleotides and antitumor effect. The present phase I trial utilized a weekly x 3 bolus infusion schedule, repeated every 5 weeks. Biochemical measurement of GTP and dGTP were performed in patients at each dose level. Twelve patients received 16 courses of the drug in doses ranging from 1100 to 2050 mg/m2 weekly x 3. The dose limiting toxicities were pericarditis and clinical symptoms suggestive of a more generalized serositis (chests and abdominal pain). Other toxicities included reversible elevations in CPK (MM band only) and SGOT, nausea, vomiting, and arthralgias. Neurotoxic effects were generally mild, including headaches, anxiety, and malaise. Only 1 of 6 patients evaluated for tiazofurin's biochemical activity showed a sustained depletion of guanine nucleotide pools. No antitumor activity was observed. The maximally tolerated dose of tiazofurin on this intermittent weekly x 3 schedule was 1650 mg/m2. Toxicity and the overall lack of biochemical and biologic effect at clinically achievable doses may preclude further clinical evaluation of this drug on weekly schedule. The toxicities observed in our study were similar to those reported for phase I investigations using a considerably higher dose intensity with daily x 5 schedules.

AB - Tiazofurin (2-B-D-ribofuranosylthiazole-4-Carboxamide: NSC 286193) is a nucleoside antimetabolite that acts as a potent inhibitor of IMP dehydrogenase resulting in a guanine nucleotide deprivation. Recent in vivo biochemical observations in rats bearing hepatoma suggested a correlation between depletion of guanine nuncleotides and antitumor effect. The present phase I trial utilized a weekly x 3 bolus infusion schedule, repeated every 5 weeks. Biochemical measurement of GTP and dGTP were performed in patients at each dose level. Twelve patients received 16 courses of the drug in doses ranging from 1100 to 2050 mg/m2 weekly x 3. The dose limiting toxicities were pericarditis and clinical symptoms suggestive of a more generalized serositis (chests and abdominal pain). Other toxicities included reversible elevations in CPK (MM band only) and SGOT, nausea, vomiting, and arthralgias. Neurotoxic effects were generally mild, including headaches, anxiety, and malaise. Only 1 of 6 patients evaluated for tiazofurin's biochemical activity showed a sustained depletion of guanine nucleotide pools. No antitumor activity was observed. The maximally tolerated dose of tiazofurin on this intermittent weekly x 3 schedule was 1650 mg/m2. Toxicity and the overall lack of biochemical and biologic effect at clinically achievable doses may preclude further clinical evaluation of this drug on weekly schedule. The toxicities observed in our study were similar to those reported for phase I investigations using a considerably higher dose intensity with daily x 5 schedules.

UR - http://www.scopus.com/inward/record.url?scp=0025323344&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0025323344&partnerID=8YFLogxK

M3 - Article

VL - 6

SP - 51

EP - 61

JO - Selective Cancer Therapeutics

JF - Selective Cancer Therapeutics

SN - 1043-0733

IS - 1

ER -