Abstract

Nitrosoureas pose a clear carcinogenic risk to patients exposed during treatment for a variety of malignant diseases; however, little is known about the risk factors for carcinogenesis in exposed individuals or about the actual level of mutagen exposure in humans. The cumulative risk of leukemia in patients treated with nitrosoureas is as high as 6% at 5 years, making it important to study the critical factors leading to malignant transformation as well as to develop methods to either reduce the risk or to identify individuals at high risk. Mutagenicity of nitrosoureas is mediated in part by the formation of various DNA adducts of which 06alkylguanine is one of the most mutagenic and carcinogenic. Cells are dependent on the repair protein 06alkylguanine-DNA alkyltransferase (alkyltransferase) to avoid the mutagenic and carcinogenic effects of 06alkylguanine. The biochemical characteristics of the alkyltransferase make it ideal to measure in situ carcinogen exposure and susceptibility to mutagenic damage. This protein transfers the alkyl groups from 06alkylguanine to itself, and in the process becomes inactivated in a stoichiometric fashion. Because cells do not experience mutagenic damage from 06alkylguanine adducts until all of the alkyltransferase has been inactivated, the level of alkyltransferase activity is a critical factor in the mutagenicity of many N-nitroso compounds. Furthermore, in cultured cells, inactivation of the alkyltransferase is directly proportional to exposure dose. We propose to develop a test for nitrosourea exposure based on measurement of alkyltransferase activity in peripheral blood leukocytes. We will determine whether changes in alkyltransferase activity are a useful monitor of exposure and individual susceptibility to nitrosoureas. Specifically, we will (1) Characterize the ability of the assay to detect exposure to different nitrosoureas; (2) Validate the method by monitoring exposure in patients receiving defined amounts of chemotherapeutic nitrosoureas. These patients provide a unique opportunity to correlate known levels of exposure with changes in cellular levels of alkyltransferase and to study the kinetics of alkyltransferase depletion and recovery. (3) Begin pilot studies to correlate changes in alkyltransferase activity with acute toxicity and/or secondary tumors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA043688-01
Application #
3422816
Study Section
(SRC)
Project Start
1986-09-30
Project End
1987-09-29
Budget Start
1986-09-30
Budget End
1987-09-29
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106