Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to such unmet need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (Antabuse), an old alcohol-aversion drug effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify ditiocarb-copper complex as the metabolite of disulfiram responsible for anticancer effects, and provide methods to detect its preferential accumulation in tumours and candidate biomarkers for impact in cells and tissues. Finally, our functional and biophysical analyses reveal the long-sought molecular target of disulfiram’s tumour suppressing effects as NPL4, an adapter of p97/VCP segregase essential for protein turnover involved in multiple regulatory and stress-response cellular pathways.

A large number of women survive a diagnosis of breast cancer. Knowledge of their risk of developing a new primary cancer is important not only in relation to potential side effects of their cancer treatment, but also in relation to the possibility of shared etiology with other types of cancer. A cohort of 525,527 women with primary breast cancer was identified from 13 population-based cancer registries in Europe, Canada, Australia and Singapore, and followed for second primary cancers within the period 1943-2000. We used cancer incidence rates of first primary cancer for the calculation of standardized incidence ratios (SIRs) of second primary cancer. Risk of second primary breast cancer after various types of nonbreast cancer was also computed. For all second cancer sites combined, except contralateral breast cancer, we found a SIR of 1.25 (95% CI 5 1.24-1.26) on the basis of 31,399 observed cases after first primary breast cancer. The overall risk increased with increasing time since breast cancer diagnosis and decreased by increasing age at breast cancer diagnosis. There were significant excesses of many different cancer sites; among these the excess was larger than 150 cases for stomach (SIR 5

Hydrochlorothiazide use is associated with a substantially increased risk of NMSC, especially SCC.

Cancer risk in patients with cirrhosis could be modified by factors such as changes in hormonal levels, impaired metabolism of carcinogens, or alteration of immunological status. We investigated the risk of liver and various forms of cancer in patients with cirrhosis in a follow-up study. We identified 11,605 1-year survivors of cirrhosis from the files of the Danish National Registry of Patients (NRP) from 1977 to 1989. Occurrence of cancer through 1993 was determined by linkage to the Danish Cancer Registry. For comparison, the expected number of cancer cases was estimated from national age-, sex-, and site-specific incidence rates. Overall, 1,447 cancers were diagnosed among the study subjects, as compared with 708.1 expected, to yield a standardized incidence ratio (SIR) of 2.0 (95% CI: 1.9 to 2.2). In all diagnostic subgroups of cirrhosis, the risk of primary liver cancer, mainly hepatocellular carcinoma, was markedly elevated, with 245 observed cases and an overall 36-fold elevated risk (59.9-fold elevated for hepatocellular carcinoma and 10-fold for cholangiocarcinoma). Substantial and persistent excesses during follow-up were seen for all types of cancer associated with tobacco and alcohol habits (cancer of the lung, larynx, buccal cavity, pharynx, pancreas, urinary bladder, and kidney), while moderate excesses were seen for cancers of the colon and breast. The latter, however, were not complemented by any decrease in the risk of prostate cancer (SIR: 1.0; 95% CI: 0.7 to 1.3). A slightly increased risk was seen for testis cancer, but disappeared after 10 years. We found evidence of an increased risk for liver and several extrahepatic cancers in patients with cirrhosis. Although part of this increase is likely attributable to alcohol and tobacco consumption, our study opens up the possibility that cirrhosis plays a role in the carcinogenesis of types of cancer other than liver cancer. (HEPATOLOGY 1998;28:921-925.)

There is increasing evidence of an inverse association between use of nonsteroidal anti-inflammatory drugs (NSAIDs) and risk of colorectal cancer. However, data regarding other cancer sites are limited. Using data from the population-based North Jutland Prescription Database and the Danish Cancer Registry, we compared cancer incidence among 172 057 individuals prescribed nonaspirin NSAIDs with expected incidence (based on county-specific cancer rates) during a 9-year study period. A total of 6081 incident cancer cases were diagnosed among NSAID users vs 5722 expected (standardised incidence ratio (SIR) 1.1, 95% confidence interval (CI)1.0 -1.1). The SIRs for colon and rectal cancer among persons who obtained 10 or more prescriptions were 0.7 (95% CI 0.6 -0.9) and 0.6 (95% CI 0.4 -0.9), respectively. Similarly, reduced risk estimates were found for stomach (SIR 0.7, 95% CI 0.4 -1.1) and ovarian cancer (SIR 0.7, 95% CI 0.4 -1.0). Standardised incidence ratios for other cancers among those with 10 or more prescriptions tended to be close to 1.0, except for lung, kidney, and prostate cancers with SIRs of 1.3 (95% CI 1.1 -1.6), 1.4 (95% CI 0.9 -2.1), and 1.6 (95% CI 1.3 -2.0), respectively. We found protective associations of NSAIDs against colon, rectal, stomach, and ovarian cancer. Reasons for the increased risk for some cancer sites are not clear.

Among 14 088 patients, with a primary diagnosis of Parkinson's disease during the period 1977 -98 identified from the National Register of Patients, 1282 cancers were subsequently recorded in the Danish Cancer Registry, compared with 1464 expected, with a standardised incidence ratio (SIR) of 0.88 (95% confidence interval (CI), 0.8 -0.9). Significantly reduced risks were found for smokingrelated cancers, for example, cancers of the lung (SIR, 0.38), larynx (0.47) and urinary bladder (0.52), although moderate reductions in risk were also seen for several nonsmoking-related cancers. In contrast, increased risks were seen for malignant melanoma (SIR, 1.95; 95% CI, 1.4 -2.6), nonmelanocytic skin cancer (1.25; 1.1 -1.4) and breast cancer (1.24; 1.0 -1.5). The observed cancer pattern supports the hypothesis that constituents of tobacco smoke inhibit or delay the development of Parkinson's disease, but a low smoking prevalence appears to be only part of the explanation for the decreased cancer incidence. The increased relative risks of melanoma and nonmelanoma skin cancer are not likely to be artefactual, but further investigations of potential mechanisms are warranted.

Hydroxymethylglutaryl-CoA reductase inhibitors (statins) have been linked with potential chemopreventive effects; however, the data are conflicting. We conducted a population-based cohort study using data from the Prescription Database of North Jutland County and the Danish Cancer Registry for the period 1989 -2002. In a study population of 334,754 county residents, we compared overall and site-specific cancer incidence among 12,251 statin users (>2 prescriptions) with cancer incidence among nonusers and users of other lipid-lowering drugs (n ‫؍‬ 1,257). Statistical analyses were based on age-standardization and Poisson regression analysis, adjusting for age, gender, calendar period and use of NSAIDs, hormone replacement therapy and cardiovascular drugs. We identified 398 cancer cases among statin users during a mean follow-up period of 3.3 years (range 0 -14 years). The age-and gender-standardized incidence rates of cancer overall were 596 per 100,000 Key words: statins; cancer incidence; risk; epidemiology; cohort study Inhibitors of hydroxymethylglutaryl-CoA reductase (statins) have been linked with several beneficial effects beyond their effect on cardiovascular disease, including reductions in risk of dementia, 1-3 fractures 4 -7 and cancer. 8,9 However, the data on cancer risk are conflicting. In a review of rodent carcinogenicity tests, Newman and Hulley reported that statins and fibrates initiate or promote cancer in rats and mice. 10 In most of the reviewed studies, however, the doses used were substantially higher than the recommended maximum doses for humans, and the employed bioassays were criticised for being inadequate to predict carcinogenicity in humans. 11 In contrast, several recent studies of human cancer cell lines and animal tumour models indicate that statins may have chemopreventive properties by inducing apoptosis and inhibiting tumour growth and metastasis. 12-21 Although a growing body of laboratory data thus indicate that statins may protect against cancer, 8,9 the clinical relevance of these data remain unclear. Results of clinical trials and observational studies of the association between statin use and cancer are inconsistent. [22][23][24][25][26][27][28][29][30][31][32][33][34] A few studies lend some support to a cancer-protective effect, 27,31,33,34 but the majority of the studies do not point to any substantially increased or decreased cancer risk among statin users. The reasons for the varying results are unclear but may relate to methodologic issues, including small sample sizes and short follow-up periods.Given the uncertainty about the effect of statins on cancer development and their widespread and long-term use, more data are needed on the relationship between statins and cancer. Thus, we examined cancer incidence among statin users in a populationbased cohort study in Denmark.

Objective-Investigate L-type calcium channel blockers of the dihydropyridine class for association with Parkinson's disease because these drugs traverse the blood brain barrier, are potentially neuroprotective, and have previously been evaluated for impact on PD risk.Methods-We identified 1,931 patients with a first time diagnosis for PD between 2001 and 2006 as reported in the Danish national hospital/outpatient database and density matched them by birth year and sex to 9,651 controls from the population register. Index date for cases and their corresponding controls was advanced to date of first recorded prescription for anti-Parkinson drugs, if prior to first PD diagnosis in the hospital records. Prescriptions were determined from the national pharmacy database. In our primary analyses, we excluded all calcium channel blockers prescriptions 2-years before index date/PD diagnosis.Results-Employing logistic regression analysis adjusting for age, sex, diagnosis of chronic pulmonary obstructive disorder, and Charlson co-morbidity score we found that subjects prescribed centrally acting calcium channel blockers (excludes amlodipine) between 1995 and two years prior to the index date were less likely to develop Parkinson's disease (Odds Ratio 0.73; 95% Confidence Interval 0.54-0.97); this 27% risk reduction did not differ with length or intensity of use. Risk estimates were close to null for the peripherally acting drug amlodipine and for other antihypertensive medications.Interpretation-Our data suggest a potential neuroprotective role for centrally acting L-type calcium channel blockers of the dihydropyridine class in PD that should be further investigated in studies that can distinguish between types of L-Type channel blockers.