We have been interested in the relationship of chronic inflammation with many of cancer. Our hypothesis is that phagocytes, cells important in the inflammatory process, have the ability to generate toxic products which can damage DNA and could contribute to the pathogenesis of cancer. In support of this hypothesis, we demonstrated that normal human phagocytes can produce mutations in bacteria and hamster cells (CHO cells), sister chromatid exchanges (SCEs) in CHO cells, and malignant transformation of C3H lOT1/2 cells. Further study of the mechanisms leading to these phenomena revealed that phagocyte-generated toxic oxygen metabolites (including hydrogen peroxide, and the free radicals superoxide anion and hydroxyl radical) are important in the pathogenesis of these genetic effects. We have also studied antioxidant mechanisms in the prevention of the genetic damage. While it is clear that phagocyte-generated oxidants can produce genetic injury, the nature of the specific genetic targets critical for transformation by this mechanism are unknown. Recognizing that the tumors arising from phagocyte-transformed lOT1/2 cells were a unique resource, we have been studying oncogenes in DNA samples prepared from these tumors. In doing this we have found a specific alteration in the ab1 oncogene in cells transformed by phagocyte- generated oxidants. In this proposal we will describe our plans to study and elucidate this oxidant-induced ab1 oncogene alteration. We have also found that DNA extracted from these Phagocyte-transformed lOT1/2 cells can cause transformation of NIH3T3 cells after transfection. In this proposal we describe our plan to determine the identity of these transforming genes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA047549-01A1
Application #
3191248
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1989-01-09
Project End
1991-12-31
Budget Start
1989-01-09
Budget End
1989-12-31
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Schmeichel, C J; Weitzman, S A (1991) Oxidant-induced restriction polymorphism maps to kinase region of c-abl oncogene. Free Radic Res Commun 12-13 Pt 2:761-9
Weitzman, S A; Gordon, L I (1990) Inflammation and cancer: role of phagocyte-generated oxidants in carcinogenesis. Blood 76:655-63