# POLYAMINES IN TRYPANOSOMES-FUNCTION & METABOLISM

> **NIH NIH R01** · PACE UNIVERSITY NEW YORK · 1991 · $157,925

## Abstract

Polyamines are low molecular weight amines, necessary for growth and
differentiation of cells.  We established that an inhibitor of polyamine
biosynthesis DL-alpha-difluoromethyl-ornithine (DFMO), cures model
infections of African trypanosomes (Trypanosoma brucei ssp).  Clinical
trials (>200 cases) in West Africa indicate that DFMO is >90% effective
against CNS disease refractory to Melarsoprol.  Despite these advances
these are concerns associated with further development of DFMO:  a) early
trials in East Africa indicate that DFMO refractory strains of T. b.
rhodesiense occur, b) prolonged DFMO treatment is required, and c)
resistant strains will probably emerge in West Africa.

For these reasons and based upon the trypanocidal action of DFMO, we
intend to pursue polyamine metabolism in African trypanosomes to:
a) Examine the basis for natural resistance to DFMO in T. b. rhodesiense;
b) develop alternative chemotherapy against polyamine biosynthesis and
related pathways using novel polyamine analogs and other inhibitors;
c) study the metabolism of the key intermediate, S-adenosylmethionine
(SAM) which is essential for both polyamine formation and methylation;
d) determine if SAM overproduction affects methylation of macromolecules
and is centrally involved in transformation of bloodstream
trypomastigotes.

The unexpected and dramatic rise in the methylation index (SAM:  S-
adenosylhomo-cysteine) and 5x increase in Protein Methylase II activity
suggests that SAM synthetase (which forms SAM from methionine and ATP) is
deregulated upon exposure to DFMO, potentially leading to
hypermethylation.  We will study:  1) SAM synthetase activity in
naturally transforming cells and those induced to transform by DFMO; ii)
activities of protein and nucleic acid methylases; iii) components within
the cell which become methylated during transformation.  In addition, we
will examine inhibitors of SAM synthetase and transmethylation in an
effort to determine their regulatory role during development, and as
potential targets for chemotherapy.

To further develop treatment of T. b. rhodesiense we will study DFMO
refractory isolates to determine possible mechanisms of resistance,
including the overproduction of polyamines or ODC, alterations in
trypanothione levels, changes in uptake or efflux of DFMO, and possible
amplification of the ODC gene.

## Key facts

- **NIH application ID:** 3127175
- **Project number:** 5R01AI017340-11
- **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:** 1991
- **Award amount:** $157,925
- **Award type:** 5
- **Project period:** 1981-02-01 → 1994-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3127175

## Citation

> US National Institutes of Health, RePORTER application 3127175, POLYAMINES IN TRYPANOSOMES-FUNCTION & METABOLISM (5R01AI017340-11). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/3127175. Licensed CC0.

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