# POLY(ADPR) POLYMERASE INHIBITORS IN CANCER THERAPY

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 1987 · $168,141

## Abstract

The long-term objective of this proposal is to take advantage of the
relation between NAD metabolism, poly(ADP-Ribose) synthesis and DNA repair
to design combination chemotherapy protocols for the treatment of malignant
disorders.  We have shown that nicotinamide analogs, selected for their
ability to inhibit poly(ADP-Ribose) polymerase, block the DNA repair
process, potentiate the tumorocidal effects of chemotherapeutic agents and
increase the lifespan of animals bearing L1210 leukemia or MOPC-315 myeloma.

The goals of the present proposal are to identify new, more effective
inhibitors of poly(ADP-Ribose) polymerase and optimize the dose and
scheduling of their administration to obtain synergistic interactions with
chemotherapeutic agents whose cytotoxic mechanism of action is mediated by
induction of DNA damage.  These studies will be continued in L1210 leukemia
and MOPC-315 myeloma and will be extended to solid tumors including the B16
melanoma, Lewis lung carcinoma, and EMT-6 mammary tumor.

We have shown that the nucleoside analogs, Tiazofurin and Selenazole,
interfere with maintenance of cellular NAD levels.  We will seek to develop
sequential blockade protocols in which a nicotinamide analog is used as a
direct inhibitor of poly(ADP-Ribose) polymerase and Tiazofurin or
Selenazole is used to limit substrate availability.  Combinations of these
two agents with the DNA damaging agents will be evaluated biochemically for
their ability to enhance DNA damage and biologically for their ability to
produce synergistic tumor cell killing and enhanced survival.

Our studies of the mechanisms of cell killing, following treatment with
high dose DNA damaging agents, show a dose dependent activation of
poly(ADP-Ribose) synthesis which leads to depletion of NAD and ATP pools
and consequent cell death.  This bears directly on the organ toxicity
experienced in recent clinical studies of high dose chemotherapy with
autologous marrow rescue for treatment of refractory malignancies.  We will
analyze metabolite fluxes following high dose chemotherapy to determine
whether this pathway, leading to depletion of energy metabolites, accounts
for the fatal organ toxicity.  In subsequent studies we will seek to
prevent this dose limiting toxicity by treatments designed to amplify and
protect cellular pools of pyridine nucleotides and energy metabolites.

## Key facts

- **NIH application ID:** 3173500
- **Project number:** 5R01CA035983-05
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **SAM.gov UEI:** HJMKEF7EJW69
- **Principal Investigator:** Nathan A. Berger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $168,141
- **Award type:** 5
- **Project period:** 1983-02-01 → 1988-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3173500

## Citation

> US National Institutes of Health, RePORTER application 3173500, POLY(ADPR) POLYMERASE INHIBITORS IN CANCER THERAPY (5R01CA035983-05). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3173500. Licensed CC0.

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