Manuela Gago-Dominguez

Non-steroidal anti-inflammatory drugs and bladder cancer prevention

Inclusion of phenacetin among ‘proven’ human carcinogens by the IARC in 1987, raised concerns about the carcinogenic potential of acetaminophen, its major metabolite. Acetaminophen has been implicated as a possible causal agent in the development of cancer of the renal pelvis. The bladder and renal pelvis, which derive from the same embryological structure, share the same transitional type of epithelium. Past studies have been inconclusive on the possible relationship among these analgesics and bladder cancer but no large, highly detailed study of this association has been conducted. A population-based case–control study conducted in Los Angeles, California, involved 1514 incident bladder cancer cases and an equal number of controls who were matched to the index cases by sex, date of birth (within 5 years) and race. Detailed information on medication use and prior medical conditions was collected through in-person interviews. Regular use of analgesics was not associated with an increased risk of bladder cancer in either men or women. In fact, compared with non- or irregular users, regular analgesic users were at a decreased risk of bladder cancer overall (odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.68–0.96). However, there were clear differences in both the direction and strength of the associations between the different formulation classes of analgesics and bladder cancer risk. Intake of phenacetin was positively related to bladder cancer risk in a dose-dependent manner while intake of its major metabolite in humans, acetaminophen, was unrelated to risk. Intake of all classes of NSAIDs, except pyrazolon derivatives, were negatively associated with bladder cancer risk, with suggestive evidence that the protective effect varies in strength by subcategories of formulation. Acetic acids seemed to exhibit the strongest protective effect, whereas aspirin/other salicylic acids and oxicam showed the weakest protection.

Use of permanent hair dyes and bladder-cancer risk.

A population‐based case‐control study was conducted in Los Angeles, California, which involved 1,514 incident cases of bladder cancer and an equal number of age‐, sex‐ and ethnicity‐matched controls. Information on personal use of hair dyes was obtained from 897 cases and their matched controls. After adjustment for cigarette smoking, a major risk factor for bladder cancer, women who used permanent hair dyes at least once a month experienced a 2.1‐fold risk of bladder cancer relative to non‐users (p for trend = 0.04). Risk increased to 3.3 (95% CI = 1.3–8.4) among regular (at least monthly) users of 15 or more years. Occupational exposure to hair dyes was associated with an increased risk of bladder cancer in this study. Subjects who worked for 10 or more years as hairdressers or barbers experienced a 5‐fold (95% CI = 1.3–19.2) increase in risk compared to individuals not exposed.

Opposing effects of dietary n-3 and n-6 fatty acids on mammary carcinogenesis: The Singapore Chinese Health Study

We investigated the effects of individual fatty acids on breast cancer in a prospective study of 35u2009298 Singapore Chinese women aged 45–74 years, who were enrolled during April 1993 to December 1998 (The Singapore Chinese Health Study). At recruitment, each study subject was administered, in-person, a validated, semiquantitative food frequency questionnaire consisting of 165 food and beverage items. As of December 31, 2000, 314 incident cases of breast cancer had occurred. We used the Cox regression methods to examine individual fatty acids in relation to breast cancer risk, with adjustment for age at baseline interview, year of interview, dialect group, level of education, daily alcohol drinking, number of live births, age when menstrual periods became regular, and family history of breast cancer. Consumption of saturated, monounsaturated or polyunsaturated fat overall was unrelated to risk. On the other hand, high levels of dietary n-3 fatty acids from fish/shellfish (marine n-3 fatty acids) were significantly associated with reduced risk. Relative to the lowest quartile of intake, individuals in the higher three quartiles exhibited a 26% reduction in risk (relative risk (RR)=0.74, 95% confidence interval (CI)=0.58, 0.94)); RRs were similar across the top three quartiles of intake (0.75, 0.75, 0.72, respectively). Overall, there was no association between n-6 fatty acids and breast cancer risk. However, among subjects who consumed low levels of marine n-3 fatty acids (lowest quartile of intake), a statistically significant increase in risk was observed in individuals belonging to the highest vs the lowest quartile of n-6 fatty acid consumption (RR=1.87, 95% CI=1.06–3.27); the corresponding RR for advanced breast cancer was 2.45 (95% CI=1.20–4.97, P for trend=0.01). To our knowledge, these are the first prospective findings linking the intake of marine n-3 fatty acids to breast cancer protection.

Lipid peroxidation: a novel and unifying concept of the etiology of renal cell carcinoma (United States)

Multiple studies have noted that obese individuals are at a high risk of renal cell cancer. Similarly, numerous case–control and cohort studies have consistently reported that individuals with a history of hypertension experience an increased risk of renal cancer. In spite of this compelling body of epidemiologic data, no credible hypothesis has been advanced to explain this dual etiologic association. In this communication we propose that lipid peroxidation, which is increased in obese and hypertensive subjects, is the mechanism responsible, at least in part, for their increased risk of renal cell carcinoma. In experimental animals lipid peroxidation of the proximal renal tubules is a necessary mechanistic pathway in renal carcinogenesis induced by several different chemicals. Our hypothesis may also explain the roles of other risk (oophorectomy/hysterectomy, parity, smoking, diabetes) and protective factors (dietary antioxidants) for renal cell cancer.

Hypertension, obesity and their medications in relation to renal cell carcinoma

A population-based, case-control study was conducted in Los Angeles County, California, to investigate the inter-relationships of obesity, hypertension and medications in relation to renal cell carcinoma (RCC) risk. A total of 1204 RCC patients and an equal number of neighbourhood controls were included. Obesity was a strong risk factor for RCC. A fourfold increase in risk was observed for those with usual body mass index (kg m(-2)) of > or = 30 vs < 22. A history of hypertension was another strong, independent risk factor for RCC [odds ratio (OR) = 2.2; 95% confidence interval (CI) = 1.8, 2.6]. There was little evidence that use of diuretics was directly related to RCC development. Use of diuretics for reasons other than hypertension (primarily for weight control) was unrelated to risk among self-reported normotensive subjects (OR = 1.2; 95% CI = 0.7, 2.2). Among hypertensive subjects, heavy users of diuretics experienced similar risk as light users (OR = 0.9 among subjects with lifetime dose of > or = 137 g compared with those with lifetime dose of < 43 g). Similarly, normotensive subjects who took non-diuretic antihypertensives regularly showed no increased risk for RCC (OR = 1.1; 95% CI = 0.6-1.8), and intake among hypertensive subjects did not further increase their risk. Regular use of amphetamine-containing diet pills was associated with a twofold increase in RCC risk (95% CI = 1.4-2.8) and the risk increased with increasing dose of amphetamines. However, the fraction of cases possibly related to this exposure is small (population-attributable risk = 5%).

Cruciferous vegetables in relation to renal cell carcinoma

Little is known about the possible role of diet in the development of renal cell carcinoma (RCC). A population‐based case‐control study was conducted in non‐Asians of Los Angeles; it included 1,204 RCC patients and an equal number of neighborhood controls matched to the index cases by sex, date of birth (within 5 years) and ethnicity. Information on intake frequencies of food groups rich in vitamins A and C, various carotenoids and nitrosamines or their precursors was collected through in‐person, structured interviews. After adjustment for non‐dietary risk factors including level of education, obesity, history of hypertension, cigarette smoking and regular use of analgesics and amphetamines, there were strong inverse associations between cruciferous and dark green vegetable intakes and RCC risk (both p values for linear trend < 0.001). In terms of nutrients, there were significant inverse associations of RCC risk with consumption of a variety of carotenoids including alpha‐carotene (p < 0.001), beta‐carotene (p = 0.004), beta‐cryptoxanthin (p = 0.01) and lutein (p = 0.005). However, after adjustment for these nutrients, we still observed a significant residual effect of cruciferous vegetables, suggesting that other substances present in these vegetables may be responsible, at least partially, for the observed reduction in risk of RCC. Dietary nitrosamines and their precursors were not related to RCC risk. Int. J. Cancer 77:211–216, 1998.© 1998 Wiley‐Liss, Inc.

Role of Lipid Peroxidation in the Epidemiology and Prevention of Breast Cancer

We have recently proposed a common mechanistic pathway by which obesity and hypertension lead to increased renal cell cancer risk. Our hypothesis posits lipid peroxidation, which is a principal mechanism in rodent renal carcinogenesis, as an intermediate step that leads to a final common pathway shared by numerous observed risks (including obesity, hypertension, smoking, oophorectomy/hysterectomy, parity, preeclampsia, diabetes, and analgesics) or protective factors (including oral contraceptive use and alcohol) for renal cell cancer [Cancer Causes Control 2002;13:287–93]. During this exercise, we have noticed how certain risk factors for renal cell carcinoma are protective for breast cancer and how certain protective factors for renal cell carcinoma increase risk for breast cancer. Parity and oophorectomy, for example, are positively associated with renal cell carcinoma but are negatively associated with breast cancer. Similarly, obesity and hypertension are positively associated with renal cell carcinoma, but obesity is negatively associated with breast cancer in premenopausal women and hypertension during pregnancy is negatively associated with breast cancer. Furthermore, alcohol intake, negatively associated with renal cell carcinoma, is also positively associated with breast cancer. We propose here the possibility that lipid peroxidation may represent a protective mechanism in breast cancer. Although this runs counter to the conventional view that lipid peroxidation is a process that is harmful and carcinogenic, we present here the chemical and biological rationale, based on epidemiologic and biochemical data, which may deserve further consideration and investigation. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2829–39)

Lipid peroxidation, oxidative stress genes and dietary factors in breast cancer protection: a hypothesis

We have recently proposed that lipid peroxidation may be a common mechanistic pathway by which obesity and hypertension lead to increased renal cell cancer risk. During this exercise, we noted a risk factor swap between breast and kidney cancer (oophorectomy and increased parity, detrimental for kidney, beneficial for breast; high blood pressure, detrimental for kidney, beneficial for breast when it occurs during pregnancy; alcohol, beneficial for kidney, detrimental for breast, and so on). We have subsequently proposed the hypothesis that lipid peroxidation represents a protective mechanism in breast cancer, and reviewed the evidence of the role of lipid peroxidation on established hormonal and non-hormonal factors for breast cancer. Here, we review the evidence in support of lipid peroxidation playing a role in the relationships between dietary factors and breast cancer. Available evidence implicates increased lipid peroxidation products in the anti-carcinogenic effect of suspected protective factors for breast cancer, including soy, marine n-3 fatty acids, green tea, isothiocyanates, and vitamin D and calcium. We also review the epidemiological evidence supporting a modifying effect of oxidative stress genes in dietary factor-breast cancer relationships.

Regular use of analgesics is a risk factor for renal cell carcinoma

SummaryPhenacetin-based analgesics have been linked to the development of renal pelvis cancer and renal cell carcinoma (RCC). The relationship between non-phenacetin types of analgesics and kidney cancer is less clear, although laboratory evidence suggests that these drugs possess carcinogenic potential. A population-based case–control study involving 1204 non-Asian RCC patients aged 25–74 and an equal number of sex-, age- and race-matched neighbourhood controls was conducted in Los Angeles, California, to investigate the relationship between sustained use of analgesics and risk of RCC according to major formulation categories. Detailed information on medical and medication histories, and other lifestyle factors was collected through in-person interviews. Regular use of analgesics was a significant risk factor for RCC in both men and women (odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.4–1.9 for both sexes combined). Risks were elevated across all four major classes of analgesics (aspirin, non-steroidal anti-inflammatory agents other than aspirin, acetaminophen and phenacetin). Within each class of analgesics, there was statistically significant increasing risk with increasing level of exposure. Although there was some minor variability by major class of formulation, in general individuals in the highest exposure categories exhibited approximately 2.5-fold increase in risk relative to non- or irregular users of analgesics. Subjects who took one regular-strength (i.e. 325 mg) aspirin a day or less for cardiovascular disease prevention were not at an increased risk of RCC (OR = 0.9, 95% CI = 0.6–1.4).

Polymorphisms in DNA repair genes, smoking, and bladder cancer risk: findings from the International Consortium of Bladder Cancer

Tobacco smoking is the most important and well-established bladder cancer risk factor and a rich source of chemical carcinogens and reactive oxygen species that can induce damage to DNA in urothelial cells. Therefore, common variation in DNA repair genes might modify bladder cancer risk. In this study, we present results from meta-analyses and pooled analyses conducted as part of the International Consortium of Bladder Cancer. We included data on 10 single nucleotide polymorphisms corresponding to seven DNA repair genes from 13 studies. Pooled analyses and meta-analyses included 5,282 cases and 5,954 controls of non-Latino white origin. We found evidence for weak but consistent associations with ERCC2 D312N [rs1799793; per-allele odds ratio (OR), 1.10; 95% confidence interval (95% CI), 1.01-1.19; P = 0.021], NBN E185Q (rs1805794; per-allele OR, 1.09; 95% CI, 1.01-1.18; P = 0.028), and XPC A499V (rs2228000; per-allele OR, 1.10; 95% CI, 1.00-1.21; P = 0.044). The association with NBN E185Q was limited to ever smokers (interaction P = 0.002) and was strongest for the highest levels of smoking dose and smoking duration. Overall, our study provides the strongest evidence to date for a role of common variants in DNA repair genes in bladder carcinogenesis.