# TUMOR PROMOTERS EFFECTING BASE MODIFICATION IN DNA

> **NIH NIH R01** · NEW YORK UNIVERSITY · 1992 · $149,993

## Abstract

Reactive oxygen species (ROS) have been implicated as playing an important
role in tumor promotion and in progression of benign to malignant tumors.
ROS produced by tumor promoter-activated polymorphonuclear leukocytes
(PMNs) are mutagenic and carcinogenic, and cause formation of the oxidized
bases thymidine glycol, 5-hydroxymethyl-2'-deoxyuridine (HMdU) and 8-
hydroxyl-2'-deoxyguanosine (8-OHdG) in DNA, which are lethal, mutagenic and
miscoding.  The long-term objective of this work is to elucidate the
mechanism by which ROS are induced in tumor promotion and the role of
oxidative DNA damage in carcinogenesis.  The main hypothesis to be tested
is that the formation of ROS and oxidative DNA damage constitutes a common
denominator among tumor promoters and that they are tumor-promoting
equivalents in the action of complete carcinogens, which require oxidative
metabolism.  This hypothesis is based on our recent findings, which show
that in vivo treatment of SINCERE mice with tumor promoters of the phorbol
ester type results in the production of H2O2 and oxidized bases in the DNA
of epidermal cells.  We also showed that a treatment of mouse skin with
7,12-dimethylbenz(a)anthracene (DMBA), which led to tumor development, also
caused prolonged inflammation, H2O2 production and formation of oxidized
bases in the epidermal DNA.  Their levels were comparable to those mediated
by the potent tumor promoter TPA (12-O-tetradecanoylphorbol-13-acetate),
but apparently with different rates of formation and disappearance.  Aims
of this study are:  1)  To determine whether TPA and non-TPA type tumor
promoters, and polycyclic aromatic hydrocarbons induce PMN infiltration,
H2O2. Hmdu and 8-Ohdg formation in epidermis of SINCERE mice;  2)  To find
whether anti-tumor promoters suppress DMBA-mediated inflammatory responses,
formation of oxidized DNA bases and chemotactic factors (IL-1 and IL-8),
and have an effect on chemotaxis of PMNs; 3)  To establish whether TPA- and
DMBA-induced Hmdu and 8-Ohdg disappear from epidermal DNA with different
rates and effects of anti-tumor promoters on that disappearance; 4)  To
determine whether DMBA-mediated formation of H2O2, Hmdu and 8OHdG are
comparable in SINCERE and C57BL/6J mice; and 5)  To establish whether
oxidative DNA damage is required for the TPA-mediated expression of the
competence genes c-fos and c-myc.  Hmdu and 8-OHdC will be assayed by HPLC
and 3H-postlabeling with [3H]acetic anhydride, cytokines in sera by binding
of antibodies labeled with a fluorochrome, and gene expression by Northern
blot analysis and nuclear run-off transcription.

## Key facts

- **NIH application ID:** 3175728
- **Project number:** 2R01CA037858-07A2
- **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:** 1992
- **Award amount:** $149,993
- **Award type:** 2
- **Project period:** 1985-04-01 → 1995-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3175728

## Citation

> US National Institutes of Health, RePORTER application 3175728, TUMOR PROMOTERS EFFECTING BASE MODIFICATION IN DNA (2R01CA037858-07A2). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3175728. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*