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.3-methylcholanthrene ͉ antineoplastic agents ͉ cyclophosphamide ͉ cancer inhibition ͉ cancer prediction
A cancer DNA phenotype, identical to the DNA structure of tumors, has been identified in the prostate glands of certain healthy men over 55 years of age. We now show that the same DNA signature exists in normal tissues adjacent to tumors. This finding implies that the phenotype is maintained in normal prostate cells from its inception through tumor development. The presence of the phenotype in tumors, adjacent normal cells, and in the normal prostate cells of certain older men suggests that it is a potentially critical factor in tumor development and may serve as an early biomarker for cancer risk assessment. Intervention to inhibit the development of the phenotype in healthy men, or to eliminate it once formed, may suppress or even prevent tumor formation.cancer phenotype ͉ DNA structure ͉ cancer biomarkers ͉ cancer prediction and intervention ͉ Fourier transform-infrared spectroscopy U sing established Fourier transform-infrared (FT-IR) statistical models (1-5), we have demonstrated previously a cancer DNA phenotype in the limbs of mice 10 weeks after injecting the carcinogen 3-methylcholanthrene (4). This phenotype was identified in normal tissues 8 weeks before tumor formation. Strikingly, administration of the prodrug cyclophosphamide every 10 days after 3-methylcholanthrene injection delayed tumor formation by about 30% and almost completely suppressed development of the phenotype, thus suggesting that it may also be inhibited by other intervention strategies with less toxic side effects (4).In a previously reported study (2), a similar cancer DNA phenotype was identified in the prostate glands of certain healthy older men (55-80 years old). Both studies showed differences between the DNA of normal tissues and those tissues with the phenotype characterized by significant alterations in the base and backbone structures. In the prostate, for example, the development of the phenotype appeared to be age-related in that no evidence was found for it in men younger than 36 years of age. A statistical comparison of the FT-IR spectrum of the cancer phenotype with the DNA spectrum of normal prostate tissues of the healthy younger men revealed a broad array of differences in base structures (e.g., N-H and C-O), as well as in vertical base-stacking interactions. Various differences were also found in the phosphodiester-deoxyribose backbone (2). These differences likely arise from constituents in the microenvironment (e.g., reactive oxygen species) capable of inducing conformational changes in the backbone via disruptions in the planar base structure (6).The previous evidence (2) for a cancer DNA phenotype in certain older men suggests that this structure may respond differently in transcription and replication from the DNA of younger men, thus potentially increasing cancer risk. We now report that the cancer DNA phenotype in the prostate glands of older men is indistinguishable from the phenotype found in histologically normal tissues surrounding tumors. This finding implies that the phenotype is structurally stable, ...
Fourier transform-infrared statistical models have the proven ability to identify subtle structural changes in DNA at various stages of tumor development. Using these models, we show evidence for a metastatic cancer DNA phenotype in histologically normal prostate tissues surrounding metastasizing tumors. Strikingly, the DNA base and backbone structures of the metastatic phenotype are indistinguishable from those of the metastasizing prostate tumors but distinctly different from the structure recently reported for the primary cancer DNA phenotype. These findings suggest that the DNA structure linked to the development of metastasis is preordained in progenitor cells relatively early in multistep tumorigenesis. The substantial structural differences found between the primary and metastatic cancer DNA phenotypes suggest that each evolves through a separate pathway. The metastatic phenotype is potentially an early predictor of metastatic disease. Interventions that inhibit its formation would be expected to also inhibit the development of metastatic tumors.metastasis ͉ cancer prediction ͉ cancer intervention ͉ Fourier transforminfrared spectroscopy ͉ DNA structure M etastasis is commonly believed to result from the clonal selection of a few rare cells in a tumor population (1-3). An alternative mechanistic model for metastasis was suggested on the basis of DNA microarray studies implying that the proclivity for metastasis is hardwired in progenitor cells (4-6). One study (4) showed that gene expression profiles in primary breast tumors are strikingly similar to those in distant metastases of the same patients. Another study (7), which used laser capture microdissection in combination with DNA microarrays, found marked similarities at the transcriptional level among the distinct stages of breast tumor progression. Collectively, these studies (4-7) call into question classical theories of metastasis but support the concept that its characteristic features are preordained early in tumorigenesis (8).Statistical models of Fourier transform-infrared (FTIR) spectra of DNA have the unique ability to discriminate between a variety of subtle changes in base functional group and backbone structures as well as in the conformational properties of DNA (9). These structural changes have been found in various stages of primary and metastatic tumor development (10-15). In a recent study (16), the FTIR technology effectively differentiated between the prostate DNA of histologically normal tissues, nonmetastasizing primary tumors, metastasizing primary tumors, and distant metastases of prostatic carcinomas. The first evidence for a primary cancer DNA phenotype in normal tissues was obtained in this study (16). FTIR technology also has been used to distinguish between the DNA of normal granulocytes and granulocytes from patients with myelodysplastic syndrome (17). It was also used recently to identify a primary cancer DNA phenotype in carcinogen-treated mice occurring Ϸ8 weeks before palpable tumors and to show that cyclophosphamide su...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.