CLINICAL PHENOTYPE TARGETED ANTIFOLATE CHEMOTHERAPY

Project: Research project

Project Details

Description

The drug sensitivity and clinical outcome of human leukemias is highly
dependent on their cell lineage of origin. This proposal will aim to
define biochemical phenotypes with respect to drug metabolism that
account for the lineage-specific response to antifolates exhibited by
human leukemias. Polyglutamylation of classical and novel antifolates by
the enzyme Folylpolyglutamate synthetase (FPGS) is essential to their
pharmacological activity, resulting in prolonged intracellular retention
and increased cytotoxicity. The proposed studies will test the
hypothesis that the response of human leukemias to antifolates depend
upon the expression of FPGS. We will investigate the biochemical and
molecular basis for the reported clinical observation that a lineage-
specific increase in FPGS activity occurs after in vivo leukemic blasts'
exposure to these drugs. These studies will define the role of substrate
affinity for FPGS and inhibition of key folate-metabolizing enzymes, and
the effects of non-polyglutamylatable antifolates and natural folates.
Similar studies with normal hematopoietic progenitors after exposure to
antifolates will define the potential role of FPGS in drug selectivity.
Further, changes in DNA methylation and FPGS mRNA expression in normal
bone marrow cells and leukemic blasts will be investigated. To evaluate
the clinical significance of these results, FPGS and polyglutamylation
related parameters will be determined in clinical samples from antifolate
sensitive and resistant leukemias. The clinical relevance of FPGS in
antifolate response will also be tested by growth factor-induced
upregulation of FPGS in resistant myeloid leukemic blasts' exposed to
these agents, and after transfection of an inducible expression system
encoding hFPGS to an "enzyme deficient" resistant leukemic phenotype.
Overall, this proposal should provide a definitive answer to: 1. How
important is FPGS in the clinical response to antifolates? 2. What are
the effects of novel antifolates on leukemic blasts' FPGS expression, and
do these differ in sensitive vs resistant phenotypes vs normal bone
marrow progenitors? 3. Is the lineage-specific expression of FPGS an
important clinical determinant of a biochemical phenotype predictor of
antifolate tumor response?
StatusFinished
Effective start/end date2/1/971/31/02

Funding

  • National Cancer Institute: $102,266.00
  • National Cancer Institute: $101,719.00
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute

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