Previous work by Malins and others, using gas chromatography-mass spectrometry with selected ion monitoring (GC-MS/SIM) and, more recently, Fourier transform-infrared (FT-IR) spectroscopy in combination with statistical analysis, has demonstrated profound modifications of DNA bases and phosphodrester-deoxyribose structures during carcinogenesis, even before there is any histopathological evidence of tumors. These changes have been attributed primary to free radicals, such as the hydroxyl radical (OH). Data obtained with this approach have sharply distinguished between, e.g., livers from fish exposed to an environment contaminated with chemical carcinogens and livers of fish from a clean reference area, between benign prostatic hyperplasia (BPH) and prostatic carcinoma, as well as between breast tissue from a mammary carcinoma and breast tissue removed during reduction of the size of noncancerous breast. We now propose experiments in two different mouse systems with different tumor etiologies, chemically induced rhabdomyosarcomas and mammary tumor virus (MTV)-assoicated breast carcinomas.
Our first aim i s to confirm and extend the previous work by applying the FT-IR/statistics technology to analyze DNA as cell populations change from normalcy via a preneoplastic stage to primary tumors and metastases. Second, we shall evaluate the ability of scavengers of free radicals to decrease DNA base damage, as detected by FT-IR spectroscopy, and thereby inhibit/delay carcinogenesis. Third, we shall evaluate how two chemotherapeutic drugs with different modes of action affect detectable DNA lesions, using the FT-IR technology, and attempt to correlate this with their activity in tumor formation.
| Malins, Donald C; Anderson, Katie M; Gilman, Naomi K et al. (2004) Development of a cancer DNA phenotype prior to tumor formation. Proc Natl Acad Sci U S A 101:10721-5 |
| Malins, Donald C; Hellstrom, Karl Erik; Anderson, Katie M et al. (2002) Antioxidant-induced changes in oxidized DNA. Proc Natl Acad Sci U S A 99:5937-41 |
| Malins, D C; Polissar, N L; Ostrander, G K et al. (2000) Single 8-oxo-guanine and 8-oxo-adenine lesions induce marked changes in the backbone structure of a 25-base DNA strand. Proc Natl Acad Sci U S A 97:12442-5 |
