# TUMOR PROMOTERS EFFECTING BASE MODIFICATION IN DNA

> **NIH NIH R01** · NEW YORK UNIVERSITY · 1989 · $171,069

## Abstract

There is increasing evidence that tumor promoters may act, at
least in part, by induction of active oxygen species' which are
capable of oxidizing DNA bases.  We found that there is a
correlation between the in vivo first-stage tumor promoting
activity, production of H2O2 by promoter-stimulated human
polymorphonuclear leukocytes (PMNs) and formation of oxidized
bases in DNA exposed to them.  Iron ions present in a complex
with EDTA or with transferrin were needed for the formation of
5-hydroxymethyl-2'-deoxyuridine (HMdU) and thymidine glycol
(dTG).  Autologous plasma substantially potentiated DNA damage.
12-0-tetradecanoyl-phorbol-13-acetate (TPA) also caused
formation of HMdU in the DNA of HeLa cells, the amount of
which was increased in the presence of PMNs.  One of the main
objectives of this proposal is to determine whether there is also a
correlation between the in vivo first-stage promoting potency and
formation of HMdU, dTG and 8-hydroxy-2'-deoxyguanosine
(80HdG) in the DNA of HeLa cells, as well as in Bloom's syndrome
and normal human fibroblasts.  The in vivo formation of oxidized
bases will be tested by the application of TPA, mezerein (Mez)
and 12-0-retinoyl-phorbol-13-acetate (RPA) to mouse skin
(SENCAR and C57BL/6).  DNA will be isolated from the
epidermal cells, digested to 2'-deoxyribonucleosides, and analyzed
by HPLC for HMdU, dTG and 80HdG.  The second objective is to
determine whether the promotional effects of complete
carcinogens that require oxidative metabolism also involve
formation of active oxygen species and oxidized bases.  We have
found that incubation of rat liver microsomes with benzo(a)pyrene
(B(a)P) causes a dose-dependent production of H2O2 and
formation of HMdU and dTG in co-incubated DNA that is
inhibited by catalase.  The non-carcinogenic PAHs pyrene and
anthracene were inactive.  To achieve this objective, the effects
of carcinogens (B(a)P, 7,12-dimethyl-benz(a)anthracene and 5-
methylchrysene) and co-carcinogens (benzo(e)pyrene and 6-
methylchrysene) on formation of H2O2 and of oxidized bases in
DNA will be tested in various systems.  These include incubations
with induced and uninduced mouse liver microsomes (same mouse
strains as above), with HeLa cells with and without microsomes,
and treatment of mouse skin with carcinogenic PAHs.  Formation
and persistance of oxidized bases in DNA of PAH-treated mouse
skin will be compared to those resulting from treatment with
tumor promoters.

## Key facts

- **NIH application ID:** 3175732
- **Project number:** 5R01CA037858-05
- **Recipient organization:** NEW YORK UNIVERSITY
- **SAM.gov UEI:** NX9PXMKW5KW8
- **Principal Investigator:** Krystyna Frenkel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1989
- **Award amount:** $171,069
- **Award type:** 5
- **Project period:** 1985-04-01 → 1991-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3175732

## Citation

> US National Institutes of Health, RePORTER application 3175732, TUMOR PROMOTERS EFFECTING BASE MODIFICATION IN DNA (5R01CA037858-05). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3175732. Licensed CC0.

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