# SECOND GENERATION INHIBITORS OF POLYAMINE BIOSYNTHESIS

> **NIH NIH R01** · UNIVERSITY OF HELSINKI · 1987 · $62,230

## Abstract

The major goal of this proposal is to develop and test "second generation
inhibitors of polyamine biosynthesis, most notably compounds that inhibit
adenosylmethionine decarboxylase.  Although methylglyoxal
bis(guanylhydrazone) (MGBG) has extremely narrow therapeutic index and the
compound exerts effects, which in all likelihood are unrelated to the
biosynthesis of the natural polyamines, it still remains the compound of
choice, when the synthesis of new inhibitors ar designed.  In the MGBG
molecule two very important properties are combined:  it is extremely
potent competitive inhibitor of adenosylmethionine decarboxylase, an enzyme
needed for the synthesis of spermidine and spermine, and it utilizes the
polyamine-deprivation inducible transport system.  Thanks to our very
recent syntheses of new MGBG analogs, we have got a much better insight
into the functional structure of MGBG molecule as regards the inhibition of
adenosylmethionine decarboxylase, the use of the native polyamine carrier
for cellular transport, the inhibition of diamine oxidase and the capabiity
of replacing intracellularly bound polyamines.  We have already synthesized
several analogs of MGBG, designed synthetic routes for many further
compounds and started to test a few compounds in combination with
difluoromethylornithine (DFMO) in animal tumor screens.  We have also
designed experimental approaches to evaluate the significance in vivo of
the diamine oxidase inhibition produced by the diguanidines.  Furthermore,
based on historical evidence, both experimental and clinical, and supported
by our preliminary experiments, we have uncovered a possible biochemical
basis for some major side-effects of MGBG, such as hypoglycemia and
disturbances affecting muscle tissue.  These side-effects could conceivably
be based upon an inhibition of carnitine-dependent fatty acid oxidation by
bis(guanylhydrazones).  Finally, using hybridization techniques (with the
aid of a pBR322 plasmid containing an ornithine decarboxylase gene
insertion) we will elucidate the nature of cellular compensatory mechanisms
triggered by polyamine deprivation at the level of gene expression.  With
the aid of sandwich hybridization method we developed for ornithine
decarboxylase, we have shown that in tumor cells growing under the pressure
of DFMO, the expression of the enzyme is greatly enhanced.

## Key facts

- **NIH application ID:** 3175496
- **Project number:** 5R01CA037695-03
- **Recipient organization:** UNIVERSITY OF HELSINKI
- **SAM.gov UEI:** YM1UNKPWTJL9
- **Principal Investigator:** JUHANI E JANNE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $62,230
- **Award type:** 5
- **Project period:** 1985-04-01 → 1988-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3175496

## Citation

> US National Institutes of Health, RePORTER application 3175496, SECOND GENERATION INHIBITORS OF POLYAMINE BIOSYNTHESIS (5R01CA037695-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3175496. Licensed CC0.

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