# INHIBITORS OF PURINE NUCLEOSIDE PHOSPHORYLASE

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 1991 · $91,957

## Abstract

Inhibitors of purine nucleoside phosphorylase (PNP) have been sought as
specific lympholytic agents because of the association of T cell deficiency
states with inherited deficiency of PNP enzyme acitivity.  The depletion of
T cells in this disorder has been attributed to the selective metabolism of
the PNP substrate, 2'-deoxyguanosine, to dGTP.  Thus, analogs of
2'-deoxyguanosine which are not substrates for PNP are also of potential
utility as immunosuppressive agents and in the chemotherapy of T cell
lymphoproliferative disorders.  We propose to utilize
9-Beta-D-arabinosylguanine (ara-G), an analog of 2'-deoxyguanosine which is
not readily degraded by PNP activity, to sort out the metabolism and
selective toxicity of 2'-deoxyguanosine for T cells.  We will a) examine
the sensitivity of fresh and cultured leukemic cells to ara-G; b) determine
the effects of this drug on mature proliferating T4 and T8 cell
populations, as well as on mixed lymphocyte populations; c) determine the
relative roles of two 2'-deoxyguanosine phosphorylating enzymes in ara-G
phosphorylation; d) isolate T lymphoblast cDNA clones corresponding to
these phosphorylating enzymes; and e) further examine the tissue
specificity of kinase expression at the mRNA level.  We will also examine
the metabolic sequelae of partial inhibition of PNP activity induced by
weak inhibitors of the enzyme.  Recent studies have documented that partial
inhibition of PNP ativity in cultured lymphoid cells can result in
increases in guanine ribo-, rather than deoxyribonucleotide pools.  Guanine
ribonucleotide accumulation inhibits cell growth and may have major
relevance for the clinical use of these inhibitors.  We therefore intend to
study the effects of elevations and depletions in guanine ribonucleotide
pools on lymphoid and leukemic cell viability.  We will extend these
studies to further investigation of the effects of guanine ribonucleotide
depletion and cell differentiation.  These studies should elucidate some of
the biochemical effects of perturbations in guanine ribo- and
deoxyribonucleotide pools on immature and mature lymphoid cells and should
assist in the development of clinically useful lympholytic agents.

## Key facts

- **NIH application ID:** 3171838
- **Project number:** 7R01CA034085-09
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **SAM.gov UEI:** D3LHU66KBLD5
- **Principal Investigator:** Beverly S. Mitchell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1991
- **Award amount:** $91,957
- **Award type:** 7
- **Project period:** 1983-02-01 → 1995-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3171838

## Citation

> US National Institutes of Health, RePORTER application 3171838, INHIBITORS OF PURINE NUCLEOSIDE PHOSPHORYLASE (7R01CA034085-09). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3171838. Licensed CC0.

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