# FOLIC ACID METABOLISM AS A TARGET OF CHEMOTHERAPY

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 1993 · $172,025

## Abstract

The proposed project is part of a long range research effort aimed at the
development of new approaches to the chemotherapy of neoplastic diseases.
The main objective of this research is to design novel target-oriented
antifolates based on biochemical and mechanistic rationales derived from
structural and functional information and to study their effects at the
cellular and molecular level.  As specific targets, the proposed study
focuses on enzymes of two interrelated metabolic cycles, one responsible
for the formation and breakdown of the poly-gamma-glutamates of folates
and antifolates and the other the folylpolyglutamate dependent
biosynthesis of thymidylate (the TS cycle).  The proposed research sets
the following specific aims:  To design and synthesize potential
inhibitors of folylpolyglutamate synthetase, gamma-glutamyl hydrolase
(conjugase), thymidylate synthase, dihydrofolate reductase and serine
hydroxymethyl transferase; to evaluate the effects of the inhibitors on
their respective targets in cellular enzyme systems; to determine the
growth inhibitory effects of the target compounds on L1210 mouse and
CCRF-CEM human leukemia cells in culture; to study the mechanism of
selected inhibitor-enzyme interactions at the molecular level using
techniques of enzymology, X-ray crystallography, molecular mechanics and
computer graphics; to study the polyglutamylation of active antifolates
and its importance for biological activity; to correlate cellular and
cell-free enzyme inhibitory activity with in vitro cytotoxicity data and
based on these correlations select candidates for in vivo biological
testing.  The study of drug-enzyme interactions may further our knowledge
of the mechanisms of folate dependent enzymes and furnish new rationales
for inhibitor design.  Since folate metabolism is intimately linked to
nucleic acid biosynthesis and cellular proliferation, this research may
lead to important observations in tumor biology and new approaches to
cancer treatment.

## Key facts

- **NIH application ID:** 3172825
- **Project number:** 2R01CA035212-09
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **SAM.gov UEI:** LMCJKRFW5R81
- **Principal Investigator:** THOMAS I KALMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $172,025
- **Award type:** 2
- **Project period:** 1983-09-30 → 1997-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3172825

## Citation

> US National Institutes of Health, RePORTER application 3172825, FOLIC ACID METABOLISM AS A TARGET OF CHEMOTHERAPY (2R01CA035212-09). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3172825. Licensed CC0.

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