# PROMOTION OF LIVER CARCINOGENESIS BY OROTIC ACID

> **NIH NIH R01** · UNIVERSITY OF TORONTO · 1987 · $90,694

## Abstract

The present proposal stems from our recent observations that
orotic acid, a precursor of pyrimidine nucleotides is not only an
excellent liver tumor promoter but also has the potential to be a
multiorgan tumor promoter.  Unlike most of the tumor promoters,
orotic acid does not induce cell proliferation either in the liver or
in the colon, the 2 organs examined.  A new hypothesis was
postulated i.e. an imbalance in nucleotide pools such as the one
that occurs following orotic acid feeding appears to play an
important role in the promotion phase of the carcinogenic
process.

In the present proposal experiments are designed to characterize
the Orotic Acid Model of liver tumor promotion in greater detail.
In order to study the mechanism of tumor promotion, in the
present proposal experiments are designed to obtain far fewer
nodules but with increased probability of progressing to cancer.
For example rats will be initiated with diethylnitrosamine and will
be exposed to 1% orotic acid 5 or 10 weeks after initiation rather
than 1 week after initiation.  In a preliminary experiments such a
protocol resulted in 1 or 2 nodules per rat with 100% incidence of
nodules at the end of 20-40 weeks, and with 1 hepatocellular
carcinoma.

To test the multiorgan tumor potential of orotic acid, the effect
of orotic acid on the intestinal carcinogenesis initiated with
azoxymethane and on the urinary bladder carcinogenesis initiated
with N-butyl-N-(4-hydroxybutyl) nitrosamine will be tested.
Preliminary results indicated that orotic acid does indeed promote
intestinal carcinogenesis initiated with azoxymethane.

Some attractive features of this model that have human relevance
are, orotic acid is a normal cellular constituent and present in the
cow's milk in considerable quantities.  Increased orotic acid in
milk, serum and urine occurs in some hereditary disorders and
such and increase can also be achieved by metabolic disturbances
and dietary means such as high protein or amino acids intake.
Unfortunately, disturbances of this kind and high protein intake
are not uncommon in human population at large.

## Key facts

- **NIH application ID:** 3174745
- **Project number:** 2R01CA037077-04
- **Recipient organization:** UNIVERSITY OF TORONTO
- **SAM.gov UEI:** NBMSSFM3HP56
- **Principal Investigator:** DITTAKAVI S SARMA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $90,694
- **Award type:** 2
- **Project period:** 1984-04-01 → 1990-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3174745

## Citation

> US National Institutes of Health, RePORTER application 3174745, PROMOTION OF LIVER CARCINOGENESIS BY OROTIC ACID (2R01CA037077-04). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3174745. Licensed CC0.

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