allopurinol and Adenoma

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

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

To clarify whether the changes of free radicals and its scavengers are induced by thyroid disorders, we measured levels of free radical scavengers and checked O2 radical generating systems in the human thyroid gland. Thyroid specimens from patients with Graves' disease, follicular adenoma, and papillary and follicular carcinomas contained significantly higher concentrations of xanthine oxidase (XOD) and gluthathione peroxidase (GSH-PX), compared to those in the normal thyroid tissue. Catalase concentration was significantly lower in thyroid specimens from patients with Graves' disease and significantly lower in thyroid specimens from patients with follicular adenoma, compared to those in the normal thyroid tissue. Cu/Zn superoxide dismutase (Cu/Zn SOD) concentration was significantly lower in the specimens from follicular adenoma and papillary carcinoma and Mn SOD concentration was significantly higher in the specimens from papillary carcinoma than those in the normal thyroid tissue. The lipid peroxide concentration, expressed as malondialdehyde (MDA) concentration, was significantly higher in the specimens from papillary carcinoma than those in the normal thyroid tissue. These findings suggest that the levels of free radicals are increased and are scavenged and catalyzed in the thyroid of Graves' disease, whereas free radicals and lipid peroxide are not completely scavenged in papillary carcinoma tissues, suggesting that these substances affect some role in cell function of thyroid tumors.

Topics: Adenocarcinoma, Follicular; Adenocarcinoma, Papillary; Adenoma; Catalase; Free Radicals; Glutathione Peroxidase; Graves Disease; Humans; Lipid Peroxidation; Reactive Oxygen Species; Thyroid Diseases; Thyroid Gland; Thyroid Neoplasms; Xanthine Oxidase

Older patients with type I glycogen storage disease (GSD) develop hepatic adenomas that may undergo malignant transformation. Despite their similarity to oral contraceptive-related hepatic tumors, only one previous report has even mentioned hemorrhage in GSD-related hepatic tumors. We recently followed a 20-year-old patient with type Ia GSD and a 10 cm focal defect in the left lobe of the liver; angiography suggested that this was a benign adenoma. At 22 years of age, after an acute symptomatic episode, repeat studies (ultrasonography and angiography) revealed a 2 cm increase in diameter of the hepatic mass. Imminent tumor rupture was of grave concern; thus the patient was admitted to the hospital and given 2 weeks of constant glucose administration by central venous line in the hope of improving her metabolic abnormalities. After resolution of the coagulopathy and metabolic disorders, the patient safely underwent surgical enucleation of the tumor. Pathologic examination of the tumor revealed that the patient had indeed hemorrhaged into a typical hepatic adenoma that had focuses of hepatocellular dysplasia. She has done well without evidence of tumor recurrence for 3 years since the operation. We conclude that hemorrhage and malignant transformation are potential complications of GSD-related hepatic adenomas. This conclusion underscores the importance of following these patients closely as they age. Nocturnal nasogastric feeding should be considered in the hope of preventing a tumor or inducing regression. Acute symptomatic attacks should be evaluated promptly for possible tumor hemorrhage.

Topics: Adenoma; Adolescent; Adult; Allopurinol; Child; Follow-Up Studies; Glucose; Glycogen Storage Disease Type I; Hemorrhage; Humans; Infant; Infusions, Parenteral; Liver Diseases; Liver Neoplasms; Time Factors