allopurinol and Colorectal-Neoplasms

Colorectal cancer (CRC) is the third most prevalent cancer in relation to incidence and mortality rate and its incidence is considerably increasing annually due to the change in the dietary habit and lifestyle of the world population. Although conventional therapeutic options, such as surgery, chemo- and radiotherapy have profound impacts on the treatment of CRC, dietary therapeutic agents, particularly natural products have been regarded as the safest alternatives for the treatment of CRC. Kaempferol (KMP), a naturally derived flavonol, has been shown to reduce the production of reactive oxygen species (ROS), such as superoxide ions, hydroxyl radicals, and reactive nitrogen species (RNS), especially peroxynitrite. Furthermore, this flavonol inhibits xanthine oxidase (XO) activity and increases the activities of catalase, heme oxygenase-1 (HO), and superoxide dismutase (SOD) in a wide range of cancer and non-cancer cells. Based on several studies, KMP is also a hopeful anticancer which carries out its anticancer action via suppression of angiogenesis, stimulation of apoptosis, and cell cycle arrest. Due to various applications of KMP as an anticancer flavonol, this review article aims to highlight the current knowledge regarding the role of KMP in CRC.

Topics: Biological Products; Catalase; Colorectal Neoplasms; Heme Oxygenase-1; Humans; Kaempferols; Peroxynitrous Acid; Reactive Nitrogen Species; Reactive Oxygen Species; Superoxide Dismutase; Superoxides; Xanthine Oxidase

Inflammation and oxidative stress play a crucial role in the development of colorectal cancer (CRC) and interference with these mechanisms represents a strategy in CRC chemoprevention. Allopurinol, a safe molecular scavenger largely used as antigout agent, has been shown to increase survival of patients with advanced CRC and to reduce CRC incidence in long-term gout users in epidemiologic studies. We conducted a randomized, double-blind, placebo-controlled preoperative trial in subjects with colorectal adenomatous polyps to assess the activity of allopurinol on biomarkers of colorectal carcinogenesis. After complete colonoscopy and biopsy of the index polyp, 73 subjects with colorectal adenomas were assigned to either placebo or one of two doses of allopurinol (100 mg or 300 mg) and treated for four weeks before polyp removal. Change of Ki-67 labeling index in adenomatous tissue was the primary endpoint. Secondary endpoints were the immunohistochemical (IHC) expression of NF-κB, β-catenin, topoisomerase-II-α, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) in adenomatous polyps and normal adjacent colonic tissue. Compared with placebo, Ki-67 levels were not significantly modulated by allopurinol, whereas β-catenin and NF-κB expression levels decreased significantly in adenomatous tissue, with a mean change from baseline of -10.6%, 95% confidence interval (CI), -20.5 to -0.7, and -8.1%, 95% CI, -22.7 to 6.5, respectively. NF-κB also decreased significantly in normal adjacent tissue (-16.4%; 95% CI, -29.0 to -3.8). No dose-response relationship was noted, except for NF-κB expression in normal tissue. Allopurinol can inhibit biomarkers of oxidative activation in colon adenomatous polyps and normal adjacent tissue. Further studies should define its potential chemopreventive activity.

Topics: Adenoma; Adenomatous Polyps; Aged; Allopurinol; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colorectal Neoplasms; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Placebos; Preoperative Care; Preoperative Period

Regional therapy for colorectal liver metastases aimed at prolonging survival has not been tested fully in a randomized trial with untreated control subjects. This study explored the efficacy of temporary hepatic artery occlusion followed by intraportal infusion of 5-fluorouracil (5-FU) and oral allopurinol as biochemical modulators in prolonging the survival of patients with nonresectable liver metastases and no extrahepatic cancer.. Eighty-four patients were considered for randomization, of whom 24 were excluded at laparotomy because of extrahepatic cancer (n = 17) or resectable lesions (n = 5). In two patients, no cancer was identified in the liver. Thirty-two patients were allocated to receive treatment, and 28 were allocated to receive no regional or systemic treatment. Six patients were excluded after randomization because of major protocol violations.. The median survival time for patients was 17 months (range, 0-66), and for control subjects, the median was 8 months (range, 0-31). Log rank analysis demonstrated a significant survival benefit for treatment versus no treatment (P = 0.0039). (In two patients, early death was due to toxicity from the wrong dose of 5-FU and the wrong route of administration, respectively; the mean and median survival were reduced by 1 month).. This study identified a treatment modality that prolongs survival in patients with nonresectable liver metastases and no extrahepatic metastases from colorectal cancer, suggesting that control subjects receiving no therapy may not be necessary in future randomized trials.

Topics: Administration, Oral; Adult; Aged; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Constriction; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intravenous; Liver Neoplasms; Male; Middle Aged; Portal Vein; Survival Analysis; Treatment Outcome

5-Fluorouracil (5-FU) remains the most effective chemotherapeutic agent in the management of patients with metastatic colorectal cancer. Leucovorin enhances its efficacy, but also its toxicity. Cited data suggest modulation of 5-FU toxicity by high dose allopurinol. In a prospective randomized trial we assessed the ability of allopurinol in a conventional dose to modulate the toxicity of 5-FU-leucovorin combination without compromising its efficacy in 50 patients with advanced colorectal cancer. Twenty-seven patients were randomized for allopurinol but had no benefit in terms of response or reduced toxicity over the other 23. Survival of responders with colon cancer was longer than that of non-responders (p = 0.013). Although allopurinol failed to reduce 5-FU-leucovorin toxicity, it did not lower its expected efficacy.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Prospective Studies

Protection by prolonged administration of allopurinol against high-dose 5-fluorouracil (5-FU) administered with folinic acid in 74 patients with colorectal cancer was investigated. The dose of 5-FU was 700 mg/m2 per day for 5 days. Of 41 patients without previous chemotherapy, 1 had a complete response and 4 had partial responses (total 12%), 15 remained stable and 21 progressed. Mean duration of response was 7.4 (1.8-12.6) months. The most frequent toxicities were decreased granulocytes (13%), diarrhoea (37%), and stomatitis (35%), which were similar to the frequencies of other studies with lower doses of 5-FU without allopurinol. Prolonged administration of allopurinol thus gives some protection to patients with colorectal cancer who receive folinic acid plus high-dose 5-FU but responses were not better than those with conventional doses.

Topics: Aged; Allopurinol; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged

Pursuant to a promising report suggesting that an allopurinol mouthwash could have a protective effect against 5-fluorouracil (5-FU)-induced stomatitis, the authors performed a randomized, placebo-controlled, double-blind, crossover study. Seventy-seven patients, receiving their first 5-day course of chemotherapy with 5-FU +/- leucovorin, were assigned to use a mouthwash containing 20 mg of allopurinol or a placebo. The mouthwash was administered every hour for four doses commencing with each chemotherapy dose. The severity of subsequent mucositis was graded (on a 0-4 scale) by the attending physician and also by a patient-completed questionnaire. There was trend toward less mucositis in the placebo group with mean physician-judged mucositis scores of 1.3 for placebo and 1.8 for allopurinol (P = 0.07) and mean patient-judged mucositis scores of 1.5 for placebo and 1.9 for allopurinol (P = 0.15). There were no substantial differences in mucositis attributable to the two mouthwashes in the patients who crossed-over on their second cycle of chemotherapy. These data demonstrate that the tested allopurinol mouthwash regimen does not offer any protective effect against 5-FU-induced mucositis.

Topics: Allopurinol; Colorectal Neoplasms; Consumer Behavior; Double-Blind Method; Fluorouracil; Humans; Leucovorin; Middle Aged; Mouthwashes; Placebos; Randomized Controlled Trials as Topic; Stomatitis

It is now commonly accepted that the activity of 5-fluorouracil (5FU) may be potentiated by folinic acid (FA). Moreover dipyridamol (DIP) interacts with the pyrimidine salvage pathway of 5FU. In 28 patients with advanced colorectal cancer, in progression under FA-5FU, we continued treatment with FA-5FU plus DIP. FA 200 mg/m2/day. i.v. push was given before 5FU 766.52 mg/m2/day (mean dose), in 60 min infusion for 5 subsequent days. Cycle was repeated every 21 days. We noticed greater but not seriously increased toxicity by the addition of DIP. The addition of DIP did not change response rates; it seemed to increase response but not significantly.

Topics: Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Dipyridamole; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Staging

In order to improve the therapeutic index of fluorouracil (5-FU), it has been combined with cisplatin (DDP) as synergistic agent and with allopurinol (HPP) as toxicity modulator. Patients with measurable colorectal carcinoma, previously untreated by chemotherapy, were randomized to receive either 5-FU alone 500 mg/m2 push iv days 1-5 or HPP 3 x 300 mg po, days 1-5, 5-FU 800 mg/m2 push iv, days 3-5 and DDP 50 mg/m2 d6. Treatment was repeated every 4 weeks. Of 104 patients randomized, 82 were evaluable for response and survival. Six partial responses were seen in each treatment group (15%) and the median survival time was 7 months. Hematologic toxicities were comparable in both treatment groups, with a mean nadir white blood cell count of 3500/ vs. 3800/mm3 and a mean nadir platelet count of 148,000/ vs, 203,000/mm3 for HPP-5-FU-DDP and 5-FU, respectively. This study suggests that the addition of both HPP and DDP does not improve the activity of 5-FU.

Topics: Adult; Aged; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Male; Middle Aged; Survival Analysis

Topics: Allopurinol; Anorexia; Antineoplastic Agents; Cachexia; Clinical Trials as Topic; Colorectal Neoplasms; Cyproheptadine; Delayed-Action Preparations; Fluorouracil; Humans; Midwestern United States; Morphine; Mouthwashes; Neoplasms; Research; Stomatitis

The role of allopurinol usage in colorectal cancer (CRC) has no definite conclusion. The aim of this study was to explore the correlation between allopurinol usage and CRC risk in Taiwan. Using the National Health Insurance Database, we conducted a case-control study of cases who were ≥20 years old and had newly diagnosed CRC for the period from 2000 to 2013. The controls were matched to cases by age, sex, index year, comorbidities, and socioeconomic status using propensity scores. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were measured by the conditional logistic regression model. We examined 4372 cases and 4372 matched controls. A statistically significant correlation was noted between allopurinol usage and CRC risk (OR, 0.79; 95%CI, 0.69-0.90). We used the cumulative-defined daily doses (cDDDs) in a further subgroup analysis, the ORs decreased from tertile 1 (T1; low dose, <12 cDDDs), T2 (medium dose, 12 to 88.5 cDDDs), to T3 (high dose, >88.5 cDDDs). These values were 0.85 (95%CI, 0.69-1.06), 0.77 (95%CI, 0.62-0.95), to 0.76 (95%CI, 0.61-0.94). The results indicated a dose-response relationship between allopurinol usage and CRC risk (P for trend < .001). We thus inferred that patients with medium and high doses of allopurinol (≥12 cDDDs) had a statistically significantly decreased CRC risk.

Topics: Age Factors; Aged; Aged, 80 and over; Allopurinol; Asian People; Case-Control Studies; Colorectal Neoplasms; Comorbidity; Dose-Response Relationship, Drug; Female; Humans; Logistic Models; Male; Middle Aged; Odds Ratio; Risk Factors; Sex Factors; Sociodemographic Factors; Taiwan

This study aimed to determine colorectal cancer (CRC) risks among patients with gout through a follow-up study on a nationwide population-based cohort that included patients with gout and the general population in Taiwan.. From the Taiwan National Health Insurance Research Database, we identified 28 061 patients who were newly diagnosed with gout between 2000 and 2010 as the study cohort. We randomly selected 84 248 subjects matching in gender, age and baseline year as comparison cohort. The cohorts were followed up until CRC occurrence, withdrawal from the system of National Health Insurance, or Dec. 31, 2013.. Cumulative incidences and incidence rate ratios (IRRs) of CRC between two cohorts were examined. The Cox proportional hazards model was used to evaluate risk factors associated with CRC development.. During the 13-year follow-up, the incidence rate of CRC development in the gout cohort reached 2.44 per 1000 person-years, which was higher than the 2.13 per 1000 person-years in the control cohort (IRR=1.15; 95% CI 1.04 to 1.26). After adjusting for age, gender, urbanisation status and comorbidities, including hypertension, diabetes and hyperlipidaemia, gout showed no significant association with increased risk of CRC occurrence (adjusted HR=1.03; 95% CI 0.93 to 1.14).. Similar risks of CRC incidence were observed in patients with and without gout in Taiwan. Allopurinol and colchicine are commonly used as urate-lowering drug and anti-inflammation medication in Taiwan and had been shown to reduce the risk of CRC incidence. Thus, further pharmaco-epidemiological studies should be carried out to specifically assess the role of allopurinol in the relationship between gout and CRC.

Topics: Adult; Aged; Allopurinol; Colchicine; Colorectal Neoplasms; Comorbidity; Databases, Factual; Diabetes Mellitus; Female; Follow-Up Studies; Gout; Humans; Hyperlipidemias; Hypertension; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Retrospective Studies; Risk Factors; Taiwan

The connection between gout and various cancers remains unclear. We assessed the relationship between gout and colorectal cancer in a population of veterans.. We reviewed the Computerized Patient Record System of the VA New York Harbor Health Care System to assess the 10-year occurrence of colorectal cancer in patients with gout undergoing colonoscopy, versus patients with osteoarthritis but no gout.. Gout and osteoarthritis subjects were similar in age, ethnicity, body mass index, and smoking history. Among 581 gout and 598 osteoarthritis subjects with documented colonoscopies, the 10-year prevalence of colorectal cancer was significantly lower in gout (0.8%) versus osteoarthritis (3.7%) (p = 0.0008) patients. Differences in colorectal cancer rates remained significant after stratifying for nonsteroidal anti-inflammatory drug use. Among gout subjects, use of colchicine and/or allopurinol, as well as the presence/absence of concomitant osteoarthritis, did not influence colorectal cancer occurrence. On subanalysis, differences in colorectal cancer occurrence between gout and osteoarthritis subjects persisted among those who underwent diagnostic (0.5% in gout vs 4.6% in osteoarthritis subjects, p < 0.001) but not screening (0.9% in gout subjects vs 1% in osteoarthritis subjects, p = 1.0) colonoscopy. There was no significant difference in nonmalignant colorectal polyp occurrence between gout and osteoarthritis subjects.. Subjects with gout had decreased colonoscopy-documented occurrence of colorectal cancer compared with osteoarthritis subjects, suggesting a possible protective effect.

Topics: Allopurinol; Colchicine; Colonoscopy; Colorectal Neoplasms; Comorbidity; Correlation of Data; Early Detection of Cancer; Female; Gout; Gout Suppressants; Humans; Male; Middle Aged; Osteoarthritis; Prevalence; United States; Veterans Health; Veterans Health Services

Topics: Adenoma; Allopurinol; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Female; Humans; Male; Preoperative Care

Topics: Adenoma; Allopurinol; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Female; Humans; Male; Preoperative Care

The challenges of clinical screening of cancer risk reductive interventions ("chemopreventive") have slowed progress in deployment of therapeutics to reverse or delay the carcinogenesis process. The preoperative or window-of-opportunity design clinical trial design enrolls subjects rapidly, has short study periods, and quantifies tissue biomarkers that reflect both anti-carcinogenesis mechanism of the risk reductive intervention and key molecular events of the carcinogenesis process for a specific epithelial target. High subject screened to on study ratios reduce the efficiency and increase cost of this research strategy. Small-sized tissue samples obtained by minimally invasive endoscopic technologies limit the number of biomarkers that can be detected and quantified, forcing investigators into choosing either a broad-based but superficial multi-mechanism exploration of signaling intermediates or a more focused analysis of multiple molecular events in a linear signaling-specific pathway. More efficient strategies of the future might involve isolation and expansion of pluripotent cells from at-risk epithelium or intraepithelial neoplastic lesions. Such a strategy would allow interrogation of key carcinogenesis-associated pathways and mechanisms in representative primary single-cell cultures amenable to genomic, proteomics, or transfection-based technologies.

Topics: Adenoma; Allopurinol; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Female; Humans; Male; Preoperative Care

Activities of adenosine deaminase, 5'-nucleotidase, xanthine oxidase, superoxide dismutase, glutathione peroxidase and catalase enzymes were measured in cancerous and non-cancerous adjacent colorectal tissues from 10 patients. Activities of DNA turn-over enzymes (ADA, 5'NT and XO) were found increased and those of free-radical metabolizing enzymes (SOD, GSH-Px and CAT) decreased in cancerous tissues compared with those of non-cancerous adjacent ones. Malondialdehyde (MDA) concentrations in cancerous tissues were also found higher than those of non-cancerous tissues, which indicated accelerated lipid peroxidation in the cancerous tissues. In the correlation analysis, disordered enzymatical relations were observed between the enzymes of both metabolic pathways. Results suggest that activities of purine metabolizing enzymes increase to cope with accelerated purine metabolism in cancerous tissues and, enzymatic antioxidant defense potential of cancerous tissues decreases due to carcinogenic processes in the tissues. Reduced antioxidant defense system makes the cancerous tissue more vulnerable to toxic effects of some free-radical species.

Topics: 5'-Nucleotidase; Adenosine Deaminase; Aged; Catalase; Colorectal Neoplasms; Female; Free Radicals; Glutathione Peroxidase; Humans; Male; Malondialdehyde; Middle Aged; Models, Statistical; Purine Nucleotides; Superoxide Dismutase; Xanthine Oxidase

The hypoxanthine/xanthine oxidase enzyme system is known to produce the superoxide ion and hydrogen peroxide during the hydroxylation of hypoxanthine via xanthine to uric acid. When chelated iron is included in this system, superoxide reduces iron (III) to iron(II) and the iron(II)-chelate further reacts with hydrogen peroxide to form the highly reactive hydroxyl radical. Because of the limitations of colourimetric and spectrophotometric techniques by which, to date, the mechanisms of hydroxyl radical formation in the hypoxanthine/xanthine oxidase system have been monitored, a high performance liquid chromatography method utilizing the ion-pair reagent tetrabutylammonium hydroxide and salicylic acid as an aromatic probe for quantification of hydroxyl radical formation was set up. In the hypoxanthine/xanthine oxidase system the major products of hydroxyl radical attack on salicylic acid were 2,5-dihydroxy benzoic acid and 2,3-dihydroxy benzoic acid in the approximate ratio of 5:1. That the hydroxyl radical is involved in the hydroxylation of salicylic acid in this system was demonstrated by the potency especially of dimethyl sulphoxide, butanol and ethanol as scavengers. Phytic acid, which is considered to be an important protective dietary constituent against colorectal cancer, inhibited hydroxylation of salicylic acid at a concentration one order of magnitude lower than the classical scavengers, but was only effective in the absence of EDTA. The method has been applied to the study of free radical generation in faeces, and preliminary results indicate that the faecal flora are able to produce reactive oxygen species in abundance.

Topics: Chromatography, High Pressure Liquid; Colorectal Neoplasms; Humans; Hydroxybenzoates; Hydroxyl Radical; Hydroxylation; Hypoxanthine; Iron; Oxidation-Reduction; Reactive Oxygen Species; Salicylates; Salicylic Acid; Xanthine Oxidase

Twenty-four patients with advanced colorectal cancer received two cycles of combination chemotherapy consisting of mitomycin 10 mg/m2 for 5 days continuous infusion and allopurinol 300 mg x 3/day p.o. for 21 days. Two patients responded partially following the two cycles of chemotherapy. Additionally, all patients received folinic acid 200 mg/m2 for 5 days as a continuous infusion. None of the nonresponders responded to the addition of folinic acid, on the contrary toxicity was increased and 2 toxic deaths were reported. We conclude that continuous infusion of folinic acid added to the combination of mitomycin and 5-fluorouracil does not improve the response rate but only enhances toxicity.

Topics: Adult; Aged; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mitomycin