# POLYAMINES IN TRYPANOSOMES--FUNCTION AND METABOLISM

> **NIH NIH R01** · PACE UNIVERSITY NEW YORK · 1988 · $157,051

## Abstract

Polyamines, low molecular weight compounds common to all cells, are
essential to growth and differentiation, acting as cofactors in
macromolecular synthesis and stabilizing nucleic acids.  This study aims to
a) explore regulation of synthesis of polyamines and related nucleosides in
pathogenic African trypanosomes; b) ascertain functions of  polyamines in
these parasites; c) develop novel single drug and combination chemotherapy
incorporating polyamine antagonists; d) correlate changes in polyamine
synthesis to life-cycle stages of Trypanosoma b. brucei.

The research will exploit our preliminary findings in which a specific
polyamine antagonist, DL-Alpha-difluoromethylornithine (DFMO) cured a
short-term murine infection, and DEMO + the antitumor agent bleomycin cured
a long term CNS infection.  A key enzyme of polyamine metabolism is
ornithine decarboxylase (ODC), the target of DFMO.  Since ODC activity is
carefully regulated in most cells, the study will examine ODC induction as
it relates to bloodstream/culture trypomostigote transformation by charting
ODC changes in bloodstream forms on subculture, and also in a lower
trypanosomatid.  A polyamine-activated protein kinase, phosphorylating an
endogenous substrater in T. b. brucei will be examined as ODC regulator.  A
byproduct of polyamine synthesis, methylthioadenosine (MTA), may be crucial
for recycling adenine and methionine.  A key enzyme in this pathway, MTA
phosphorylase will be studied in T. b. brucei, as will novel inhibitors of
the enzyme, and intermediates in MTA breakdown.

Trypanosomatid DNA plymerases are polyamine-activated.  Their interaction
with kDNA as template primers, and effects of cationic trypanocides which
mimic polyamines, will be examined.  To guide combination chemotherapy,
effects of polyamine depletion of the the parasite on uptake of
polyamine-like antitumor and other agents will be determined.

These studies will correlate in vivo, in vitro (whole cell), crude and
purified enzyme studies, and employ radio-tracer techniques as well as
thin-layer and high-precision liquid chromatography.  Ion-exchange and
affinity chromatography would be used in ODC, protein kinase and DNA
polymerase studies.  We would further investigate polyamine-cationic drug
interaction in vivo by combination therapy with cationic antitumor agents +
polyamine antagonists.  We hope thereby to uncover additional targets for
chemotherapy and to develop novel agents or combinations of agents useful
for human and veterinary trypanosomiases.

## Key facts

- **NIH application ID:** 3127173
- **Project number:** 5R01AI017340-08
- **Recipient organization:** PACE UNIVERSITY NEW YORK
- **SAM.gov UEI:** Y738A5L1B3V1
- **Principal Investigator:** CYRUS J BACCHI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1988
- **Award amount:** $157,051
- **Award type:** 5
- **Project period:** 1981-02-01 → 1989-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3127173

## Citation

> US National Institutes of Health, RePORTER application 3127173, POLYAMINES IN TRYPANOSOMES--FUNCTION AND METABOLISM (5R01AI017340-08). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3127173. Licensed CC0.

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