METABOLISM OF TIAZOFURIN IN HUMAN LEUKEMIA CELLS

  • Jayaram, Hiremagalur, (PI)

Project: Research project

Description

Our recent studies on the treatment of twenty-four patients with end stage
acute myeloid leukemia and myeloid blast crisis of granulocytic leukemia
with tiazofurin revealed that in this poor prognosis group of patients five
attained complete seen in four others. The effect lasted for 3 to 10
months with intermittent drug treatment. We have demonstrated that only
50% of the patients respond; therefore, we need a predictive test to spare
those patients who might not benefit. Therefore, the first Specific Aim of
the proposal is to test the hypothesis that an in vitro test to predict the
sensitivity of leukemic cells of patients to tiazofurin can be developed on
the basis of biochemical targets. To test this hypothesis, we will
elucidate the relationship between the predictive test, which would be
based on the levels of TAD (thiazole-4-carboxamide adenine dinucleotide,
active metabolite of tiazofurin) and the associated decrease in the GTP
pools (target of tiazofurin action); and tiazofurin metabolizing enzyme
activities (tiazofurin phosphorylation, NAD pyrophosphorylase and TAD
phosphodiesterase). To achieve this goal the project plans to separate and
enrich leukemic cells from leukemic patients and their counter parts (from
healthy volunteers) and incubate in vitro with radiolabeled tiazofurin.
The second Specific Aim of this project is to test the hypothesis that the
regulation of tiazofurin metabolism and the extent of conversion of
tiazofurin to TAD is correlated with hematologic response in refractory
leukemia. To test this hypothesis blood samples will be obtained from
patients undergoing tiazofurin therapy and the concentration of TAD in
leukemic cells will be correlated with GTP levels and hematologic response.
The activities of tiazofurin metabolizing enzymes will be determined in
duplicate cell samples prepared for the predictive test. The third
Specific Aim of this 5-year program is to test the hypotheses that the
emergence of tiazofurin resistant leukemic cells is regulated by tiazofurin
metabolism. to test this hypothesis we will elucidate the regulation of
TAD by monitoring the extent of TAD synthesis by tiazofurin metabolizing
enzymes, and the targets, IMP dehydrogenase activity and GTP pools in
leukemic cells obtained from patients sensitive and clinically refractory
to tiazofurin. This program should yield novel conceptual approaches to
the treatment of human leukemia.
StatusFinished
Effective start/end date1/1/9112/31/94

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

tiazofurin
Leukemia
Guanosine Triphosphate
Nicotinamide-Nucleotide Adenylyltransferase
IMP Dehydrogenase
Blast Crisis

Keywords

  • Medicine(all)