8-hydroxy-2--deoxyguanosine and Intestinal-Neoplasms

The exact antineoplastic effects of calcium and vitamin D(3) in the human colon are unclear. Animal and in vitro studies show that these two agents reduce oxidative stress; however, these findings have never been investigated in humans. To address this, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial to test the effects of calcium and vitamin D(3) on a marker of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine (8-OH-dG), in the normal colorectal mucosa. Patients (N = 92) with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d calcium and/or 800 IU/d vitamin D(3) versus placebo over 6 months. Overall labeling and colorectal crypt distribution of 8-OH-dG in biopsies of normal-appearing rectal mucosa were detected by standardized automated immunohistochemistry and quantified by image analysis. After 6 months of treatment, 8-OH-dG labeling along the full lengths of colorectal crypts decreased by 22% (P = 0.15) and 25% (P = 0.10) in the calcium and vitamin D(3) groups, respectively, but not in the calcium plus vitamin D(3) group. The estimated treatment effects were strongest among participants with higher baseline colon crypt vitamin D receptor expression (P = 0.05). Overall, these preliminary results indicate that calcium and vitamin D(3) may decrease oxidative DNA damage in the normal human colorectal mucosa, support the hypothesis that 8-OH-dG labeling in colorectal crypts is a treatable oxidative DNA damage biomarker of risk for colorectal neoplasms, and provide support for further investigation of calcium and vitamin D(3) as chemopreventive agents against colorectal neoplasms.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenoma; Adult; Aged; Biomarkers, Tumor; Calcium Carbonate; Calcium, Dietary; Cholecalciferol; Deoxyguanosine; Dietary Supplements; DNA Damage; Double-Blind Method; Female; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Intestinal Mucosa; Intestinal Neoplasms; Male; Middle Aged; Oxidative Stress; Pilot Projects; Precancerous Conditions

Proton radiation is a major component of the radiation field in outer space and is used clinically in radiation therapy of resistant cancers. Although epidemiologic studies in atom bomb survivors and radiologic workers have established radiation as a risk factor for colorectal cancer (CRC), we have yet to determine the risk of CRC posed by proton radiation owing to a lack of sufficient human or animal data. The purpose of the current study was to quantitatively and qualitatively characterize differential effects of acute and fractionated high-energy protons on colorectal carcinogenesis.. Significantly higher intestinal tumor number and grade, along with decreased differentiation, were observed after acute radiation relative to fractionated radiation. Acute protons induced upregulation of β-catenin and Akt pathways with increased proliferative marker phospho-histone H3. Increased DNA damage along with decreased DNA repair factors involved in mismatch repair and nonhomologous end joining were also observed after exposure to acute protons.. We show increased γH2AX, 53BP1, and 8-oxo-dG, suggesting that increased ongoing DNA damage along with decreased DNA repair factors and increased proliferative responses could be triggering a higher number of intestinal tumors after acute relative to fractionated proton exposures in Apc

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; beta Catenin; Carcinogenesis; Cell Differentiation; Cell Proliferation; Colorectal Neoplasms; Cyclin D1; Disease Models, Animal; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Mismatch Repair; Dose Fractionation, Radiation; Female; Gene Expression; Genes, APC; Histones; Immunoblotting; Intestinal Neoplasms; Intestine, Small; Mice; Mice, Inbred C57BL; Neoplasms, Radiation-Induced; Proto-Oncogene Proteins c-akt; Protons; Radiation Dosage; Radiation Exposure; Space Flight; Tumor Suppressor p53-Binding Protein 1; Up-Regulation

Although large intestine (LI) cancer is the second-leading cause of cancer-related deaths in the United States, small intestine (SI) cancer is relatively rare. Because oxidative DNA damage is one possible initiator of tumorigenesis, we investigated if the SI is protected against cancer because of a more appropriate response to oxidative DNA damage compared with the LI. Sixty rats were allocated to three treatment groups: 3% dextran sodium sulfate (DSS, a DNA-oxidizing agent) for 48 hrs, withdrawal (DSS for 48 hrs + DSS withdrawal for 48 hrs), or control (no DSS). The SI, compared with the LI, showed greater oxidative DNA damage (P < 0.001) as determined using a quantitative immunohistochemical analysis of 8-oxodeoxyguanosine (8-oxodG). The response to the DNA adducts in the SI was greater than in the LI. The increase of TdT-mediated dUTP-biotin nick end labeling (TUNEL)-positive apoptosis after DSS treatment was greater in the SI compared with the LI (P < 0.001), and there was a positive correlation (P = 0.031) between DNA damage and apoptosis in the SI. Morphologically, DSS caused an extensive loss of crypt structure shown in lower crypt height (P = 0.006) and the number of intact crypts (P = 0.0001) in the LI, but not in the SI. These data suggest that the SI may be more protected against cancer by having a more dynamic response to oxidative damage that maintains crypt morphology, whereas the response of the LI makes it more susceptible to loss of crypt architecture. These differential responses to oxidative DNA damage may contribute to the difference in cancer susceptibility between these two anatomic sites of the intestine.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Apoptosis; Cell Proliferation; Deoxyguanosine; Dextran Sulfate; Disease Susceptibility; DNA; DNA Adducts; DNA Damage; Intestinal Neoplasms; Intestine, Large; Intestine, Small; Male; Oxidative Stress; Rats