Increased risk of colon cancer after external radiation therapy for prostate cancer

Radiotherapy can induce second cancers. Controversies still exist regarding the risk of second malignancies after irradiation for prostate cancer. We evaluated the risk of developing colon and rectum cancers after prostate cancer in irradiated and nonirradiated patients. Using data from the population-based Geneva cancer registry, we included in the study all men with prostate cancer diagnosed between 1980 and 1998 who survived at least 5 years after diagnosis. Of the 1,134 patients, 264 were treated with external radiotherapy. Patients were followed for occurrence of colorectal cancer up to 31 December, 2003. We calculated standardized incidence ratios (SIR) using incidence rates for the general population to obtain the expected cancer incidence. The cohort yielded to 3,798 person-years. At the end of follow-up 19 patients had developed a colorectal cancer. Among irradiated patients the SIR for colorectal cancer was 3.4 (95% confidence intervals [CI] 1.7-6.0). Compared to the general population, the risk was significantly higher for colon cancer (SIR = 4.0, 95% CI: 1.8-7.6), but not for rectal cancer (SIR = 2.0, 95% CI: 0.2-7.2). The risk of colon cancer was increased in the period of 5-9 years after diagnosis (SIR = 4.7, 95% CI: 2.0-9.2). The overall SIR of secondary cancer in patients treated with radiotherapy was 1.35 (p = 0.056). Nonirradiated patients did not have any increased risk of rectal or colon cancer. This study shows a significant increase of colon but not rectum cancer after radiotherapy for prostate cancer. The risk of second cancer after irradiation, although probably small, needs nevertheless to be carefully monitored.     

How to consider cancer: implications for the risk due to ionizing radiation

Cancers induced by ionizing radiation have no particular specificity nor genetic remarkable signature, excepting numerous multideletions. They should therefore be studied in the general field of cancer biology in its broad sense. A gap remains between the initial events like the rather well identified genomic damage and the subsequent emerging cellular clone with cancer characteristics. Intermediate steps are generally described as accumulation of mutations and epigenetic modifications leading at one point to the malignant phenotype. However we have no clear nor understandable model on these steps of malignant transformation till now. It is quite possible that specific causes (tobacco, alcohol, radiations, chemical toxics) which produce different initial abnormalities then lead to (or accelerate the entry in) the common and same way as that resulting of accumulations of damage due to ageing. Genomic instability is certainly an important factor involved in the cellular drift leading to malignant transformation. We postulate that only cells having both a high telomerase activity and a low apoptotic activity may become cancerous. The hypothesis is that cancer results from a genome reprogramming of these cells due to an oncogenic mitotic pressure which induces a loss of the differentiation control. We propose to name anti-apoptosis, in contrast to apoptosis which is the programmed death, the ultimate process by which a cell loses its tissue-related properties. The oncogenic activation may propagate to primordial genes of development resulting in emergence of a subnuclear with tumoral activity. Bio-molecular studies of embryonic development and of genome re-programming will probably allow us to better understand the mechanisms of cancer.     

Increased sensitivity of EBNA2-transformed rat fibroblasts to ionizing radiation

To clarify whether expression of Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2) correlates with sensitivity to ionizing radiation, we tested EBNA2-transformed rat fibroblast clones for their radiosensitivity to X-rays. These transformed clones reproducibly generated tumors in mice. X-irradiation suppressed the growth of the tumors, and irradiated mice survived longer than non-irradiated ones. In contrast, tumors formed by activated H-ras or E6-E7 genes of human papillomavirus type 16 (HPV16) were strongly resistant to the same dose of X-irradiation. In in vitro culture, these EBNA2-expressing clones also showed higher radiosensitivity than cell lines transformed by activated H-ras and E6-E7 genes. The averaged D_o of EBNA2-expressing clones was 2.3 times lower than that of nonexpressing and control clones. These results suggest that expression EBNA2 is responsible for the radiosensitivity. © 1996 Wiley-Liss, Inc.     

The effect of ionizing radiation on intraocular lenses

BACKGROUND: The native crystalline lens is the principal shield against ultraviolet radiation (UV), damage to the human retina. Every year in the United States, more than one million patients undergo removal of the natural lens in the course of cataract surgery (phakectomy), at which time an intraocular lens (IOL) is placed in the lens capsule. The IOL thenceforth serves as the principal barrier to ultraviolet radiation over the life of the implant, potentially for decades. The synthetic organic molecules of which IOLs are composed offer little UV protection unless ultraviolet-absorbing chromophores are incorporated into the lens material during manufacture. However, chromophores are alkenes potentially subject to radiolytic degradation. It is unknown whether ionizing radiation at clinical doses (e.g., to the brain or in the head-and-neck region) affects the UV-absorbing capacity of chromophore-bearing IOLs and consequently exposes the retina to potentially chronic UV damage. In addition, the polymers of which IOLs are composed are themselves subject to radiation damage, which theoretically might result in optical distortion in the visible light range. OBJECTIVE: To determine whether megavoltage photon ionizing radiation alters the absorption spectra of ultraviolet-shielding polymethylmethacrylate (PMMA) and organopolysiloxane (silicone) intraocular lenses (IOLs) in the UV (280 nm < or = lambda < 400 nm), visible (400 nm < or = lambda < or = 700 nm), and low-end near-infrared (700 nm < lambda < or = 830 nm) ranges.DESIGN: Prospective, nonrandomized trial of dose-paired IOL cohorts. METHODS: Fourteen IOLs, seven of PMMA (Chiron 6842B) and seven of silicone (IOLAB L141U), were paired and examined for absorption spectra in 1-nm intervals over the range lambda = 280-830 nm on a Cary 400 deuterium and quartz halogen source-lamp UV/visible spectrophotometer before and after undergoing megavoltage ionizing irradiation to doses of 2, 5, 10, 20, 40, 60, and 100 Gray, respectively. Because of artifactual aberrations inherent in analyzing convex lenses on a conventional flat-plate spectrophotometer, post-irradiation absorption spectra were subsequently reanalyzed on a Cary 300 spectrophotometer outfitted with a Labsphere Diffused Reflectance Accessory (DRA-CA-30-I) incorporating a Spectralon-coated integrating sphere. MAIN OUTCOME MEASURES: Primary: Changes in UV absorbance after irradiation. Secondary: Changes in visible and low-end near-infrared absorbance after irradiation. RESULTS: Photon ionizing radiation in the 2-Gy to 100-Gy range produced no detectable alterations in the UV (280 nm < or = lambda < 400 nm), visible (400 nm < or = lambda < or = 700 nm), or low-end near-infrared (700 nm < lambda < or = 830 nm) absorption spectra of any of the lenses irradiated. However, silicone IOLs as a group revealed peak post-irradiation UV absorption at a shorter wavelength than did PMMA IOLs, with marginally greater UV transmission at the uppermost extreme of the UV spectrum (lambda = 384.5-400 nm). CONCLUSIONS: At clinically relevant doses used in radiation therapy, megavoltage photon ionizing radiation produces no significant alterations in the absorption spectra of PMMA and silicone IOLs over the range lambda = 280- 830 nm. These findings indicate that, even at supraclinical doses, the UV-absorbing capacity of chromophore-bearing PMMA and silicone IOLs remains unimpaired. It is not clear whether the lower UV peak of silicone lenses represents a radiation effect or a peculiarity of the chromophore used in the lenses tested.     

Letrozole sensitizes breast cancer cells to ionizing radiation

Introduction  

Radiotherapy (RT) is considered a standard treatment option after surgery for breast cancer. Letrozole, an aromatase inhibitor, is being evaluated in the adjuvant setting. We determined the effects of the combination of RT and letrozole in the aromatase-expressing breast tumour cell line MCF-7CA, stably transfected with the CYP19 gene.     

Increased catechol estrogen metabolism as a risk factor for nonfamilial breast cancer.

The metabolism of estrone (E1) or estradiol-17 beta (E2) to catechols seldom has been investigated in biochemical studies related to the risk of development of human breast cancer, as a result of the extreme lability and reactivity of these hormones. A method of indirect calculation was developed in which estimated catechol estrogen excretion (ECE) from urinary excretion of E1, E2, and estriol (E3) was used, based on the obligate reciprocal relation between 16 alpha-hydroxylase activity (r3) and estrogen 2/4 hydroxylase function (r2). This relationship is expressed by r2 x r3 = K, the estrogen oxidative constant. From published data relating chiefly to 2-OH estrone excretion, K = 12.4 +/- 0.8 (standard error of the mean). Urinary E1 + E2 excretion rates reflect nonprotein-bound plasma ovarian estrogen concentrations available for cell metabolism, which influence the value of K. The equation: r2 = [E1 + E2] K/[E3 + 16 alpha OH E1] = ECE gives a median correlation coefficient between actual catechol estrogen excretion and ECE in micrograms/24 hours of +0.88 (range, 0.61 to 0.97). When tested against the best product isolation analysis of catechol estrogen excretion, ECE was 95% accurate. Using this method a metaanalysis was conducted of published fractional estrogen excretion collected from 2846 healthy women worldwide aged 15 to 59 years, with a risk of breast cancer varying fivefold. Overall ECE was 78% to 97% higher in high-risk women of all ages and menstrual cycle phases (P less than 0.001, by Wilcoxon test). With increasing cancer risk (as estimated by the authors), ECE rose linearly exponentially with a slope of 0.149 (follicular phase) and 0.136 (luteal phase). The correlation coefficient (R2) between the two variables was 0.77 and 0.57, respectively (P less than 0.05). These data derived from calculations of ECE in healthy women confirmed recent analytic results of a twofold increase in the ratio of 2-OH E1/4-OH E1 in healthy Finnish women compared with recent Japanese migrants to Hawaii. In Finnish women with breast cancer, this ratio increased further (almost twofold). Metaanalysis supported the conclusion that increased rates of oxidation of estradiol 17-beta to 2-OH catechols supply the principal proximal human mammary carcinogens active after menarche.     

Breast cancer risk polymorphisms and interaction with ionizing radiation among U.S. radiologic technologists

Genome-wide association studies are discovering relationships between single-nucleotide polymorphisms and breast cancer, but the functions of these single-nucleotide polymorphisms are unknown and environmental exposures are likely to be important. We assessed whether breast cancer risk single-nucleotide polymorphisms interacted with ionizing radiation, a known breast carcinogen, among 859 cases and 1,083 controls nested in the U.S. Radiologic Technologists cohort. Among 11 Breast Cancer Association Consortium risk single-nucleotide polymorphisms, we found that the genotype-associated breast cancer risk varied significantly by radiation dose for rs2107425 in the H19 gene (P(interaction) = 0.001). H19 is a maternally expressed imprinted mRNA that is closely involved in regulating the IGF2 gene and could exert its influence by this or by some other radiation-related pathway.     

Cell cycle and genetic background dependence of the effect of loss of BRCA2 on ionizing radiation sensitivity

Carriers of mutations in the BRCA2 gene are at a highly elevated risk of breast and other cancers. The BRCA2 gene encodes a very large protein thought to play a role in DNA repair. To examine the effect of mutation of BRCA2 on sensitivity to ionizing radiation, we used a previously described mouse model system (Brca2(Tr)) in which the Brca2 open reading frame is truncated. Mouse embryo fibroblasts carrying this mutation have a proliferative defect, which we show here can be substantially rescued by genetic ablation of p53. Proliferating Brca2(Tr/Tr)/p53(-/-) cells, like Brca2(Tr/Tr) cells, show genomic instability. We used the clonogenic survival assay, which depends on the ability of cells to proliferate, to examine the cell cycle dependence of radiation sensitivity of Brca2(Tr/Tr)/p53(-/-) compared to p53(-/-) and wild-type cells. This showed that the Brca2 mutation had little effect on cells irradiated in quiescence but sensitized proliferating cells to ionizing radiation on a p53(-/-) background. These results suggest that the major role of Brca2 in mediating cell survival after irradiation is in the S and G(2) phases of the cell cycle.     

Direct evidence for a bystander effect of ionizing radiation in primary human fibroblasts

Bystander responses underlie some of the current efforts to develop gene therapy approaches for cancer treatment. Similarly, they may have a role in strategies to treat tumours with targeted radioisotopes. In this study we show direct evidence for the production of a radiation-induced bystander response in primary human fibroblasts. We utilize a novel approach of using a charged-particle microbeam, which allows individual cells within a population to be selected and targeted with counted charged particles. Individual primary human fibroblasts within a population of 600-800 cells were targeted with between 1 and 15 helium ions (effectively, alpha-particles). The charged particles were delivered through the centre of the nucleus with an accuracy of +/- 2 micrometer and a detection and counting efficiency of greater than 99%. When scored 3 days later, even though only a single cell had been targeted, typically an additional 80-100 damaged cells were observed in the surviving population of about 5000 cells. The yield of damaged cells was independent of the number of charged particles delivered to the targeted cell. Similar results of a 2-3-fold increase in the background level of damage present in the population were observed whether 1 or 4 cells were targeted within the dish. Also, when 200 cells within one quadrant of the dish were exposed to radiation, there was a 2-3-fold increase in the damage level in an unexposed quadrant of the dish. This effect was independent of the presence of serum in the culture medium and was only observed when a cell was targeted, but not when only the medium was exposed, confirming that a cell-mediated response is involved.     

Increased chromosome-type chromosome aberration frequencies as biomarkers of cancer risk in a blackfoot endemic area

To examine whether biomarkers such as sister chromatid exchanges (SCEs) and chromosome aberrations (CAs) can predict cancer development, a nested case-control study was performed in a blackfoot endemic area with a known high cancer risk. A cohort of 686 residents was recruited from three villages in the blackfoot endemic area. Personal characteristics were collected, and venous blood was drawn for lymphocyte culture and stored in a refrigerator. The vital status and cancer development were followed using the National Death Registry, Cancer Registry, and Blackfoot Disease Registry. The follow-up period was from August 1991 to July 1995. During this 4-year period, 31 residents developed various types of cancer. Blood culture samples from nine of these subjects were unsuitable for experiments due to improper storage. Finally, a total of 22 cancer cases had cytogenetic samples that could be analyzed. Twenty-two control subjects were selected from those who did not develop cancer in the study period, and these subjects were matched to cases by sex, age, smoking habits, and residential area. The results showed that there was no significant difference in the frequencies of SCE and chromatid-type CAs between the case and control groups. However, the frequencies of chromosome-type CAs, e.g., chromosome-type gaps, chromosome-type breaks, chromosome-type breaks plus exchanges, total chromosome-type aberrations, and total frequencies of CAs in the case group, were significantly higher than those in the control group (P < 0.05). The odds ratio of cancer risk in subjects with more than zero chromosome-type breaks was 5.0 (95% confidence interval = 1.09-22.82) compared to those with zero chromosomal breaks. The odds ratios for more than zero chromosome-type breaks plus exchanges and a frequency of total chromosome-type aberrations of >1.007% were 11.0 and 12.0, respectively (P < 0.05). Subjects with a total CA frequency of >4.023% had a 9-fold increase for cancer risk. These results indicate that chromosome-type CAs are good biomarkers for the prediction of cancer development, whereas SCEs and chromatid-type CAs cannot predict cancer risk.     

Enhanced antitumor effect of combined triptolide and ionizing radiation.

PURPOSE: The lack of effective treatment for pancreatic cancer results in a very low survival rate. This study explores the enhancement of the therapeutic effect on human pancreatic cancer via the combination of triptolide and ionizing radiation (IR). EXPERIMENTAL DESIGN: In vitro AsPC-1 human pancreatic cancer cells were treated with triptolide alone, IR alone, or triptolide plus IR. Cell proliferation was analyzed with sulforhodamine B (SRB) method and clonogenic survival; comparison of apoptosis induced by the above treatment was analyzed by annexin V-propidium iodide (PI) staining. Furthermore, the expression of apoptotic pathway intermediates was measured by the assay of caspase activity and Western blot. Mitochondrial transmembrane potential was determined by JC-1 assay. In vivo, AsPC-1 xenografts were treated with 0.25 mg/kg triptolide, 10 Gy IR, or triptolide plus IR. The tumors were measured for volume and weight at the end of the experiment. Tumor tissues were tested for terminal nucleotidyl transferase-mediated nick end labeling (TUNEL) and immunohistochemistry. RESULTS: The combination of triptolide plus IR reduced cell survival to 21% and enhanced apoptosis, compared with single treatment. In vivo, tumor growth of AsPC-1 xenografts was reduced further in the group treated with triptolide plus IR compared with single treatment. TUNEL and immunohistochemistry of caspase-3 cleavage in tumor tissues indicated that the combination of triptolide plus IR resulted in significantly enhanced apoptosis compared with single treatments. CONCLUSIONS: Triptolide in combination with ionizing radiation produced synergistic antitumor effects on pancreatic cancer both in vitro and in vivo and seems promising in the combined modality therapy of pancreatic cancer.     

Polymorphisms in DNA repair genes, medical exposure to ionizing radiation, and breast cancer risk.

An epidemiologic study was conducted to determine whether polymorphisms in DNA repair genes modify the association between breast cancer risk and exposure to ionizing radiation. Self-reported exposure to ionizing radiation from medical sources was evaluated as part of a population-based, case-control study of breast cancer in African-American (894 cases and 788 controls) and White (1,417 cases and 1,234 controls) women. Genotyping was conducted for polymorphisms in four genes involved in repair of radiation-induced DNA damage, the double-strand break repair pathway: X-ray cross-complementing group 3 (XRCC3) codon 241 Thr/Met, Nijmegen breakage syndrome 1 (NBS1) codon 185 Glu/Gln, X-ray cross-complementing group 2 (XRCC2) codon 188 Arg/His, and breast cancer susceptibility gene 2 (BRCH2) codon 372 Asn/His. Allele and genotype frequencies were not significantly different in cases compared with controls for all four genetic polymorphisms, and odds ratios for breast cancer were close to the null. Combining women with two, three, and four variant genotypes, a positive association was observed between breast cancer and number of lifetime mammograms (P(trend) < 0.0001). No association was observed among women with zero or one variant genotype (P = 0.86). Odds ratios for radiation treatments to the chest and number of lifetime chest X-rays were slightly elevated but not statistically significant among women with two to four variant genotypes. The study has several limitations, including inability to distinguish between diagnostic and screening mammograms or reliably classify prediagnostic mammograms and chest X-rays in cases. Prospective studies are needed to address whether common polymorphisms in DNA repair genes modify the effects of low-dose radiation exposure from medical sources.     

Increased tumorigenicity and sensitivity to ionizing radiation upon loss of chromosomal protein HMGN1

We report that loss of HMGN1, a nucleosome-binding protein that alters the compaction of the chromatin fiber, increases the cellular sensitivity to ionizing radiation and the tumor burden of mice. The mortality and tumor burden of ionizing radiation-treated Hmgn1-/- mice is higher than that of their Hmgn1+/+ littermates. Hmgn1-/- fibroblasts have an altered G2-M checkpoint activation and are hypersensitive to ionizing radiation. The ionizing radiation hypersensitivity and the aberrant G2-M checkpoint activation of Hmgn1-/- fibroblasts can be reverted by transfections with plasmids expressing wild-type HMGN1, but not with plasmids expressing mutant HMGN proteins that do not bind to chromatin. Transformed Hmgn1-/- fibroblasts grow in soft agar and produce tumors in nude mice with a significantly higher efficiency than Hmgn1+/+ fibroblasts, suggesting that loss of HMGN1 protein disrupts cellular events controlling proliferation and growth. Hmgn1-/- mice have a higher incidence of multiple malignant tumors and metastases than their Hmgn1+/+ littermates. We suggest that HMGN1 optimizes the cellular response to ionizing radiation and to other tumorigenic events; therefore, loss of this protein increases the tumor burden in mice.