Vitamin C intake and apoptosis in normal rectal epithelium.

Apoptosis, or programmed cell death, may lower the risk of neoplasia by removing genetically damaged or mutated cells. A high rate of apoptosis has been linked to a reduced risk of colorectal adenomas; therefore, it is important to understand factors that impact apoptosis. Antioxidants (e.g., vitamin C) protect cells from harmful oxidation processes but may interfere with apoptosis by protecting genetically damaged cells from reactive oxygen species-dependent cell death. The objective of this study was to evaluate the association between vitamin C intake and apoptosis in normal rectal mucosa. Study participants were part of a large, cross-sectional study, the Diet and Health Study III. Participants were recruited from consecutive, consenting patients who underwent colonoscopy at University of North Carolina Hospitals between August 1, 1998 and March 4, 2000. Vitamin C intake, obtained from a food frequency questionnaire, included both dietary sources and vitamin supplements. Apoptosis was measured by morphological evaluation of H&E-stained sections obtained from pinch biopsy samples of normal rectal mucosa in consenting participants (n = 503). The relationship between vitamin C and apoptosis varied by adenoma status. Among individuals with adenomas, there was an inverse linear association between apoptosis and total vitamin C intake. Similarly, individuals with adenomas in the highest quintile of total vitamin C intake were substantially less likely than those in the lowest quintile to have increased colonic apoptosis (odds ratio, 0.05; 95% confidence interval, 0.01-0.46). Vitamin C was not significantly associated with apoptosis in adenoma-free patients. High vitamin C intake was associated with reduced colorectal apoptosis among individuals with adenomas in this study population. Given that high apoptosis may lower colorectal cancer risk, vitamin C supplements may be contraindicated for patients with a history of adenomas.     

Calcium plus vitamin D alters preneoplastic features of colorectal adenomas and rectal mucosa

BACKGROUND: Calcium and vitamin D are chemopreventive agents for colorectal neoplasia. Studies of the effects of calcium and vitamin D on early surrogate markers of reduced risk, such as proliferation, have been limited to evaluation of the flat colorectal mucosa. Biologic changes that may occur in colorectal adenomas after chemopreventive regimens have not been reported. METHODS: In the current study, adenomatous polyps were transected, approximately 50% were removed for histologic examination, and the remnants tattooed before the administration of either calcium carbonate (1500 mg 3 times daily) plus vitamin D(3) 400 IU or a placebo for 6 months. At study end, polyp remnants were resected completely and were used for histologic examination. Immunohistochemical staining was performed in both flat mucosa and in polyp tissue. Proliferation was assessed by MIB-1 staining; apoptosis was assessed by terminal deoxyuridine triphosphate-biotin nick-end labeling, BAK, and Bcl-2 staining; and cytokeratin AE1, vitamin D receptor, MUC5AC mucin, and galectin-3 were assessed by immunohistochemistry. RESULTS: Nineteen patients, including 11 patients in the treatment group and 8 patients in the control group, completed the study. Proliferative indices fell both in flat mucosa and in polyps in the treatment group, and there were no significant changes in the control group. Apoptosis and Bcl-2 immunostaining were unchanged in both groups, but the frequency of BAK-immunostained cells in the interior of polyps rose significantly. Vitamin D receptor staining increased slightly and significantly in flat rectal tissue in the treatment group. There were no significant changes in galectin-3 staining, but a striking reduction in MUC5AC mucin staining in polyps was observed after treatment with calcium plus vitamin D. CONCLUSIONS: The administration of a calcium plus vitamin D chemopreventive regimen resulted in several changes in adenomatous tissue that may have contributed to reduced polyp formation.     

Dietary vitamin D and vitamin D receptor level modulate epithelial cell proliferation and apoptosis in the prostate

Low vitamin D (VD) status may increase prostate cancer risk but experimental evidence for this relationship is modest. We tested whether low VD status or VD receptor (VDR) deletion influences prostate epithelial cell (PEC) biology using intact mice, castrated mice, or castrated mice treated with testosterone propionate (TP, 2.5 mg/kg BW). PEC proliferation (Ki-67 staining) and apoptosis (TUNEL method) were determined in the anterior prostate (AP). In study 1, wild-type (WT) and TgAPT(121) mice (a model of prostate intraepithelial neoplasia) were fed diets with 25, 200 (reference diet), or 10,000 IU VD/kg diet (as vitamin D(3)) prior to castration/repletion. Serum 25 hydroxyvitamin D levels were 26, 78, and 237 nmol/L in the three diet groups, respectively. Castration reduced proliferation and increased apoptosis in the AP while TP reversed these effects. Low VD diet increased proliferation in WT (+82%) and TgAPT(121) (+24%) mice while it suppressed apoptosis in WT (-29%) and TgAPT(121) (-37%) mice. This diet also increased the severity of prostate intraepithelial neoplastic lesions in the AP of intact TgAPT(121) mice. In study 2, mice with PEC-specific VDR deletion (PEC VDR KO) were examined after castration/repletion. TUNEL staining was 60% lower in castrated PEC VDR KO mice compared with castrated WT mice. In castrated mice given TP, Ki-67 staining was 2-fold higher in PEC VDR KO compared with WT mice. Our data show that low diet VDR or VDR deletion provide a prostate environment that is permissive to early procarcinogenic events that enhance prostate cancer risk.     

Calcium, phosphorus, vitamin D, dairy products and colorectal carcinogenesis: a French case--control study.

A protective effect of calcium against colorectal cancer has been described in Anglo-Saxon but not in Latin communities, and no such effect has been observed regarding adenomas. We investigated the relationship between calcium, dairy products and the adenoma-carcinoma sequence in a French region by comparing small adenoma ( < 10 mm, n = 154), large adenoma (n = 208) and polyp-free (n = 426) subjects, and cancer cases (n = 171) with population controls (n = 309). There was no protective effect of calcium against colorectal tumours except for low fat calcium and large adenomas in men (OR for highest quintile = 0.3, P for trend = 0.06). There was even a trend towards an increased risk of cancer with dairy calcium in men and non-dairy calcium in women. Vitamin D was inversely related to the risk of small adenomas in women (OR for highest quintile = 0.4, P for trend = 0.04). Regarding dairy products, only consumption of yoghurt displayed an inverse relationship with risk of large adenomas, in both men and women. These data failed to demonstrate a protective effect of calcium against colorectal carcinogenesis. They suggest that the type of dairy product might be the important factor with regard to prevention of colorectal tumours.     

Circulating vitamin D metabolites, polymorphism in vitamin D receptor, and colorectal adenoma risk.

OBJECTIVE: Vitamin D is a potential agent for the prevention of colorectal cancer possibly through mechanisms mediated by the vitamin D receptor (VDR). We investigated the association of circulating vitamin D metabolites and a genetic variant of the VDR gene with advanced colorectal adenoma, a precursor lesion of colorectal cancer. METHODS: Cases with advanced adenoma of the distal large bowel and gender- and ethnicity-matched controls with a negative sigmoidoscopy were randomly selected from participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial. Genotype analysis of the VDR TaqI polymorphism was completed on 763 cases and 774 controls. Serum levels of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] were measured in a subset of 394 cases and 397 controls. RESULTS: Serum levels of 25(OH)D were inversely associated with advanced adenoma risk in women but not in men. Comparing those in the highest quintile with those in the lowest quintile, the risk for advanced adenoma decreased by 73% in women [odds ratio (OR) = 0.27, 95% confidence interval (95% CI) = 0.11-0.69; P for trend = 0.0002], while the risk did not decrease in men (OR = 1.10, 95% CI = 0.60-2.05; P for trend = 0.85). In women, 25(OH)D levels were significantly higher in current users of hormone replacement therapy (HRT) than in former or never HRT users. Neither serum 1,25(OH)(2)D nor VDR TaqI genotype was associated with advanced adenoma risk. CONCLUSION: Higher serum 25(OH)D levels were associated with decreased adenoma risk. Serum 1,25(OH)(2)D and VDR TaqI genotype were not associated with adenoma risk.     

Calcium,vitamin D,and risk of adenoma recurrence (United States)

Objective: Few data exist regarding the association between calcium intake and adenoma recurrence, and no data exist for vitamin D. We investigated the role of dietary and supplemental sources of calcium and vitamin D in the etiology of adenoma recurrence. Methods: Analyses were conducted among 1304 male and female participants in the Wheat Bran Fiber (WBF) trial of adenoma recurrence. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results: In the fully adjusted multivariate model, the OR for participants with dietary calcium intake above 1068 versus those with intake below 698 mg/day was 0.56 (95% CI = 0.39–0.80; p-trend = 0.007). Calcium supplementation at doses above 200 mg/day did not affect risk of recurrence. Although a borderline inverse association between dietary vitamin D and recurrence was observed after adjustment for age and gender, the association weakened in the fully adjusted model (OR = 0.78 for individuals in the upper compared to the lower quartile; 95% CI = 0.54–1.13). No association was shown for supplemental sources of vitamin D. Conclusions: Results of this study indicate that a higher intake of calcium decreases the risk of adenoma recurrence by approximately 45%, whereas vitamin D has no significant effect on recurrence rates.     

Haplotype analysis of common vitamin D receptor variants and colon and rectal cancers.

Inherited variants of the vitamin D receptor (VDR) gene may influence cancer risk by altering the effect of vitamin D on cell growth and homeostasis. Studies have examined genotypes for common VDR polymorphisms, including a single nucleotide polymorphism (SNP) detected by Bsm1, a polyadenosine [poly(A)] repeat polymorphism, and a SNP detected by Fok1, as candidates for susceptibility to cancer, but most have not evaluated haplotypes for these markers. We investigated haplotypes for these polymorphisms in case-control studies of colon cancer (1,811 cases and 1,451 controls) and rectal cancer (905 cases and 679 controls). We used the expectation-maximization algorithm to estimate haplotypes for White, Hispanic, African-American, and Asian subjects, tested for differences in VDR haplotype distribution, and calculated odds ratios (OR) for association between haplotype and cancer. The distribution of haplotypes differed by race or ethnic group, but four common haplotypes accounted for the majority of alleles in all groups. VDR haplotype distributions differed between colon cancer cases and controls (P = 0.0004). The common haplotype bLF, containing Bsm1 b (Bsm1 restriction site present), poly(A) long (18-22 repeats), and Fok1 F (restriction site absent) was associated with increased risk of colon cancer, OR 1.15 (95% confidence interval, 1.03-1.28), as was the rare haplotype BLF, containing Bsm1 B (restriction site absent), poly(A) long, and Fok1 F (OR, 2.40; 95% confidence interval, 1.43-4.02). No case-control differences were detected for rectal cancer. In this analysis, haplotypes of the VDR influenced risk of colon cancer, but haplotype variables had only slightly better ability to explain case-control differences than genotype variables.     

Calcium, vitamin D, and risk for colorectal adenoma: dependency on vitamin D receptor BsmI polymorphism and nonsteroidal anti-inflammatory drug use?

Previous epidemiological studies have been inconclusive in demonstrating an inverse association among calcium, vitamin D, and risk for colorectal adenoma. The purpose of this analysis was to evaluate the associations among calcium and vitamin D and risk for incident, sporadic colorectal adenoma according to the vitamin D receptor BsmI polymorphism and nonsteroidal anti-inflammatory drug (NSAID) use. We analyzed data from a colonoscopy-based case-control study (n = 177 cases, 228 controls) conducted in North Carolina between 1995 and 1997. Adjusted odds ratios (ORs) comparing participants in the highest to those in the lowest tertiles of total calcium and vitamin D intakes were 0.64 [95% confidence interval (CI), 0.35-1.15], P(trend) = 0.14 and 0.69 (95% CI, 0.41-1.18), and P(trend) = 0.19, respectively. Adjusted ORs for those in the upper tertile of total calcium intake relative to those in the lower were 0.25 (95% CI, 0.08-0.80) among those who had a Bb genotype, 0.57 (95% CI, 0.18-1.82) among those who had a bb genotype, and 0.36 (95% CI, 0.15-0.85) among those who did not take NSAIDs. The ORs for the highest tertile of calcium intake was 0.05 (95% CI, 0.01-0.41), P(trend) < 0.01 among those who were Bb and did not take NSAIDs, and 0.16 (95% CI, 0.02-1.36), P(trend) = 0.47 among those who were bb and did not take NSAIDs. These data support the hypotheses that higher calcium intakes may decrease risk for colorectal neoplasms, and that such a relationship is more readily detectable among those who do not take NSAIDs, and may be strongest among those who have at least one vitamin D receptor BsmI b allele.     

Calcium, dairy foods, vitamin D, and colorectal cancer risk: the Fukuoka Colorectal Cancer Study

Epidemiologic evidence supporting a protective role of calcium and vitamin D in colorectal carcinogenesis has been accumulating in Western populations, but it is limited in Asian populations, whose intake of calcium is relatively low. We investigated the association of intakes of these nutrients with colorectal cancer risk in Japanese. Study subjects were participants of a large-scale case-control study in Fukuoka, Japan. Diet was assessed through interview regarding 148 dietary items by showing typical foods or dishes on the display of a personal computer. In a multivariate analysis adjusting for potential confounding variables, calcium intake was significantly, inversely associated with colorectal cancer risk (P for trend=0.01); the odds ratio for the highest versus lowest quintile of calcium intake was 0.64 (95% confidence interval, 0.45-0.93). Higher levels of dietary vitamin D were significantly associated with decreased risk of colorectal cancer among those who had fewer chances of sunlight exposure at work or in leisure (P for trend=0.02). A decreased risk of colorectal cancer associated with high calcium intake was observed among those who had higher levels of vitamin D intake or among those who had a greater chance of daily sunlight exposure, but not among those with medium or lower intake of vitamin D or among those with potentially decreased sunlight exposure. These results add to support for a joint action of calcium and vitamin D in the prevention of colorectal carcinogenesis.     

Vitamin D, calcium, and vitamin D receptor polymorphism in colorectal adenomas.

Experimental studies suggest that vitamin D and calcium protect against cancer by reducing proliferation and inducing differentiation. The effects of vitamin D and calcium may be mediated by the vitamin D receptor (VDR), which is encoded by the VDR gene. The present study investigated whether calcium intake and serum vitamin D, as an integrated measure of intake and endogenous production, were associated with risk of colorectal adenoma, known precursors of invasive colorectal cancer. In addition, the interrelation among vitamin D, calcium, and FokI polymorphism of the VDR gene was investigated. Persons (239) with histologically confirmed colorectal adenomas and 228 control individuals without colorectal adenomas confirmed by sigmoidoscopy were enrolled in this case control study conducted at the National Naval Medical Center, Bethesda, MD. We observed an inverse association of serum 25-OH vitamin D [25-(OH)D] with colorectal adenoma. With each 10 ng/ml increase of serum 25-(OH)D, the risk of colorectal adenoma decreased by 26% (odds ratio 0.74, 95% confidence interval 0.60-0.92). The results provided limited evidence for a weak association between calcium intake and colorectal adenoma (odds ratio 0.97, 95% confidence interval 0.93-1.01 per each 100-mg calcium intake). However, the inverse association of serum 25-(OH)D with colorectal adenoma is suggested to be stronger in subjects with calcium intake above the median (P for multiplicative interaction 0.13). The VDR FokI polymorphism was not significantly associated with colorectal adenoma and did not modify the effect of vitamin D or calcium. In conclusion, the study results suggested a protective effect for vitamin D on colorectal adenoma.     

Serum vitamin D,vitamin D binding protein,and lung cancer survival

ObjectivesVitamin D may prolong cancer survival by inhibiting tumor progression and metastasis, however, there are limited epidemiologic studies regarding the association between circulating 25-hydroxyvitamin D (25(OH)D) and lung cancer survival. The aim of this study was to examine the relationship between serum 25(OH)D and lung cancer specific survival and to evaluate whether vitamin D binding protein (DBP) concentration modified this association.Materials and methods25(OH)D and DBP were measured in fasting serum samples from 500 male lung cancer cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for lung cancer related death according to quartiles of season-specific 25(OH)D, DBP, and the molar ratio of 25(OH)D:DBP, a proxy for free circulating 25(OH)D.ResultsComparing highest to lowest quartiles, serum 25(OH)D (HR = 1.18; 95% CI: 0.89–1.56) and DBP (HR = 0.95; 95% CI: 0.71–1.26) were not associated with lung cancer survival and DBP concentration did not modify the association with 25(OH)D (p for interaction = 0.56). There was suggestion of an association between higher serum 25(OH)D and better survival from adenocarcinoma (HR = 0.64; 95% CI: 0.17–2.45) and small cell carcinoma (HR = 0.55; 95% CI: 0.21–1.45), but these estimates were based on a relatively small number of cases.ConclusionSerum 25(OH)D was not associated with overall lung cancer survival regardless of DBP concentration, however, these findings should be examined in other studies that include women and subjects with higher 25(OH)D levels.     

Calcium, vitamin D, sunshine exposure, dairy products and colon cancer risk (United States)

Objective: Epidemiologic studies on calcium, vitamin D and colon cancer are inconsistent, whereas experimental studies more regularly show a protective effect. To evaluate potential sources of inconsistencies, data from a large case–control study were analyzed, stratifying on potential effect modifiers. Methods: Data were collected by certified interviewers in Northern California, Utah and Minnesota. Analyses included 1993 incident colon cancer cases and 2410 population-based controls. Multivariate logistic regression models included age, sex, BMI, family history, physical activity, intake of energy, dietary fiber, aspirin and NSAIDs. Results: Dietary calcium was inversely associated with colon cancer risk in men (OR highest vs lowest quintile = 0.6, 95% CI = 0.5–0.9) and women (OR = 0.6, 95% CI = 0.4–0.9). No statistically significant associations were observed for dietary vitamin D or sunshine exposure. Consumption of total low-fat dairy products was associated with a statistically significantly decreased risk in men and women (ORs highest vs lowest category of intake = 0.8 and 0.7 respectively). Calcium supplement use was inversely associated with risk in both sexes (ORs use vs non-use = 0.8). Vitamin D supplements were inversely associated with risk in men (OR = 0.5) and women (OR = 0.6) but confidence limits included 1.0. Conclusions: These data provide additional support of an inverse association between high levels of calcium intake and colon cancer risk.     

Serum levels of vitamin D metabolites and the subsequent risk of colon and rectal cancer in Finnish men

Experimental and human epidemiologic data suggest a protective rolefor vitamin D in large bowel cancer. To investigate this association, weconducted a nested case-control study within a Finnish clinical trial cohort.Cases (n = 146) were participants diagnosed with primary adenocarcinoma ofthe large bowel. Controls were matched (2:1) to cases on age, date ofbaseline blood draw, and study clinic. Prediagnostic serum levels of thevitamin D metabolites, 25-hydroxyvitamin D (25-OH D), and1,25-dihydroxyvitamin D (1,25-DIOHD) were used as primary exposure measures.The baseline geometric-mean serum level of 25-OH D was 11.6 percent lower incases than in controls (12.2 cf 13.8 ug/l, P = 0.01) while serum levels of1,25-DIOH D did not differ by case-control status. No association was seenbetween serum levels of 1,25-DIOH D and large bowel cancer risk. However, theestimated relative risk (RR) of large bowel cancer decreased with increasinglevel of serum 25-OH D and the associa tion was more pronounced for rectalcancer (55 cases; RR by quartile = 1.00, 0.93, 0.77, 0.37; trend P = 0.06).Neither exclusion of early cases nor multivariate adjustment for potentialconfounders materially altered these estimates. There was no evidence ofeffect modification by level of 1,25-dihydroxyvitamin D or with other knownrisk-factors for large bowel cancer.     

Calcium,vitamin D,dairy products,and risk of colorectal cancer in the Cancer Prevention Study II Nutrition Cohort (United States)

Objective: Calcium, vitamin D, and dairy product intake may reduce the risk of colorectal cancer. We therefore examined the association between these factors and risk of colorectal cancer in a large prospective cohort of United States men and women. Methods: Participants in the Cancer Prevention Study II Nutrition Cohort completed a detailed questionnaire on diet, medical history, and lifestyle in 1992–93. After excluding participants with a history of cancer or incomplete dietary information, 60,866 men and 66,883 women remained for analysis. During follow-up through 31 August 1997 we documented 421 and 262 cases of incident colorectal cancers among men and women, respectively. Multivariate-adjusted rate ratios (RR) were calculated using Cox proportional hazards models. Results: Total calcium intake (from diet and supplements) was associated with marginally lower colorectal cancer risk in men and women (RR = 0.87, 95% CI 0.67–1.12, highest vs lowest quintiles, p trend = 0.02). The association was strongest for calcium from supplements (RR = 0.69, 95% CI 0.49–0.96 for 500 mg/day vs none). Total vitamin D intake (from diet and multivitamins) was also inversely associated with risk of colorectal cancer, particularly among men (RR = 0.71, 95% CI 0.51–0.98, p trend = 0.02). Dairy product intake was not related to overall risk. Conclusions: Our results support the hypothesis that calcium modestly reduces risk of colorectal cancer. Vitamin D was associated with reduced risk of colorectal cancer only in men.     

Vitamin D intake,vitamin D receptor polymorphisms,and breast cancer risk among women living in the southwestern U.S.

No studies of dietary vitamin D intake and vitamin D receptor (VDR) have been conducted comparing breast risk among Hispanic women and non-Hispanic white (NHW) women. We investigated the association between vitamin D intake and breast cancer in a population-based case–control study of 1,527 NHW and 791 Hispanic breast cancer cases diagnosed in 1999–2004 in Arizona, New Mexico, Utah, and Colorado, and 1,599 NHW and 922 Hispanic age-matched controls. Vitamin D intake was assessed using food frequency questionnaires, and associations with breast cancer were adjusted for age, ethnicity, state, education, body mass index, smoking, age at menarche, age at first birth, parity, hormone exposure, height, and physical activity using logistic regression. BsmI, Poly A and FokI vitamin D receptor (VDR) genotypes were also measured. Dietary vitamin D intake was positively associated with breast cancer (highest vs. lowest quartile (Q ₄ vs. Q ₁): odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.15–1.60; P _trend = 0.003), whereas vitamin D supplement use was inversely associated with breast cancer (10+ μg/day vs. none: OR = 0.79, 95% CI = 0.65–0.96, P _trend = 0.01). Similar patterns in risk were observed by ethnicity and menopausal status. Positive associations with dietary vitamin D intake and inverse associations with supplement use were observed for ER+/PR+ and ER−/PR− breast cancers, but not for ER+/PR− disease. BsmI genotype significantly modified the association between dietary vitamin D and breast cancer overall. Future research is needed to better understand potential differences in breast cancer risk by vitamin D source and hormone receptor status.     

Serum vitamin D concentration,vitamin D-related polymorphisms,and colorectal cancer risk

Serum 25-hydroxyvitamin D (25(OH)D) has been demonstrated to be associated with risk of colorectal cancer (CRC). However, it remains unclear whether this association was modified by vitamin D-related polymorphisms. We evaluated association of serum 25(OH)D concentration with CRC risk among 403 170 participants from UK Biobank Project. Two variants of vitamin D binding protein (VDBP), rs4588 and rs7041, were included to estimate the binding affinity of 25(OH)D to VDBP, and three variants of vitamin D receptor (VDR), rs11568820, rs2228570 and rs1544410, which may influence VDR activity, were also investigated. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During 4 957 677 person-years of follow-up, 5053 incident CRC cases were documented. Higher serum 25(OH)D concentrations were significantly associated with lower CRC incidence in a dose-response manner, with HR (95% CIs) being 0.94 (0.91-0.97) per 1 SD increment of serum 25(OH)D level (P_trend < .001). When separated by anatomic site, we observed a significant association between higher 25(OH)D and lower incidence of colon cancer (P_trend < .001), but not rectal cancer (P_trend = .880). The inverse associations between 25(OH)D level and CRC risk were demonstrated in almost all individuals carrying different GC or VDR genotypes, except for those with rs1544410 TT or rs4588 TT genotypes. There was no significant interaction between any single variant, or haplotypes of GC or VDR, and 25(OH)D level. Our findings suggest the potential benefits of maintaining adequate vitamin D for CRC prevention, particularly for tumors from colon.     

High intrinsic apoptosis,but not radiation-induced apoptosis,predicts better survival in rectal carcinoma patients

PURPOSE: An important feature of malignant tumors is the disturbance in the balance between proliferation and cell death. We evaluated the relevance of intrinsic and radiation-induced apoptosis and proliferation for prognosis in rectal cancer patients. METHODS AND MATERIALS: Patients were selected from a study that randomized for preoperative radiotherapy (RT). Apoptosis and proliferation were scored using specific antibodies in immunohistochemistry. The number of positive cells per square millimeter of carcinoma cells was determined in 98 randomly selected tumors, of which 45 had been irradiated. For the survival analyses, a cohort of 104 patients without positive circumferential resection margins was selected. RESULTS: In nonirradiated patients, high levels of intrinsic apoptosis correlated with better local control (p = 0.04) and better cancer-specific survival (p = 0.02). RT increased the median amount of apoptosis from 10.8 to 21.5 cells/mm(2) (p = 0.004), but this was not predictive for survival. The amount of proliferative cells was not altered after RT and had no influence on prognosis. CONCLUSIONS: Intrinsic apoptosis correlated with both local control and cancer-specific survival, but proliferation was not predictive for prognosis. However, although RT increased apoptosis, its prognostic value was lost after RT. This is possibly because in rectal cancer, the proliferative status of tumors is always high and the aggressiveness of the tumor is determined by the number of "spontaneous" apoptotic tumor cells.