Development of a cancer DNA phenotype prior to tumor formation.
Using the carcinogen 3-methylcholanthrene (MCA), we demonstrate with Fourier transform-infrared spectroscopy that a cancer DNA phenotype is produced well in advance of palpable tumors. We further demonstrate that the administration of cyclophosphamide markedly inhibits the development of the cancer phenotype and concomitantly delays tumor formation. MCA, injected into the hind legs of mice, produced a variety of significant structural changes in the nucleotide bases and phosphodiester-deoxyribose backbone, as reflected in a substantial (34%) difference between the mean DNA spectra of the control and the MCA-injected mice. Strikingly, 57 days before the mean appearance of tumors, we could not distinguish the DNA structure of the histologically normal tissues of the MCA-injected mice from the DNA structure of the tumor tissues. This finding indicates the early development of a cancer phenotype. Confirmatory evidence was obtained when tissues from a group of mice injected with both MCA and cyclophosphamide did not manifest the cancer phenotype, and their mean DNA structure closely resembled that of the control mice. Accordingly, we propose that the cancer DNA phenotype, as evinced by Fourier transform-infrared spectroscopy, is a promising early indicator of tumor formation, and we postulate that agents capable of inhibiting this phenotype may delay or prevent carcinogenesis.
Malins
Donald C
DC
Biochemical Oncology Program, Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, USA. dmalins@pnri.org
Anderson
Katie M
KM
Gilman
Naomi K
NK
Green
Virginia M
VM
Barker
Edward A
EA
Hellström
Karl Erik
KE
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D005260:Female; D008748:Methylcholanthrene / Q000008:administration & dosage* / Q000009:adverse effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018482:Muscle, Skeletal / Q000166:cytology / Q000473:pathology; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D017550:Spectroscopy, Fourier Transform Infrared
D018906:Antineoplastic Agents, Alkylating; D008748:Methylcholanthrene; D003520:Cyclophosphamide; D004247:DNA