allopurinol and Breast-Neoplasms

Hypoxia, or a lack of oxygen, occurs in 50-60% of solid human tumours. Clinical studies have shown that the presence and extent of hypoxia in a tumour cannot be predicted by size or histopathological stage but it is predictive of a poor outcome following radiotherapy, chemotherapy and surgery. However, as a physiological feature of tumours, it can be exploited and researchers have developed many hypoxia-selective chemotherapies or bioreductive drugs that are in varying stages of clinical development. These agents are prodrugs that have two key requirements for their biological activation: they require the reductive environment of a hypoxic tumour cell and the appropriate complement of cellular reductase enzymes. To overcome tumour heterogeneity in reductase enzyme levels and enhance bioreductive drug metabolism a gene therapy strategy can be employed. We have reviewed this field and also present our own pre-clinical research using gene therapy to enhance bioreductive drug treatment for the treatment of cancer. We have specifically focused on studies enhancing lead clinical bioreductive drugs. We consider the metabolic requirements for their activation and we highlight the key in vivo studies supporting the future clinical development of hypoxia-targeted gene-directed enzyme prodrug therapy.

Topics: Alkylating Agents; Animals; Anthraquinones; Breast Neoplasms; Cytochrome P-450 Enzyme System; Cytochromes; Cytochromes b5; Female; Genetic Therapy; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Mice; Mitomycin; Neoplasms; Nitric Oxide Synthase; Prodrugs; Xanthine Oxidase

Topics: Allopurinol; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Squamous Cell; Colonic Neoplasms; Cyclophosphamide; Dactinomycin; Diethylstilbestrol

40 cases postmenopausal women with breast cancer constituted the study group and 20 sex and age matched formed the control group. The study group of untreated patients showed nonsignificant decrease in molybdenum but significant decrease in blood xanthine oxidase and riboflavin levels. Tamoxifen treated patients showed nonsignificant increase in molybdenum, after 3 months, significant increase after 6 months and significant increase in xanthine oxidase and riboflavin levels. Thus tamoxifen when given in breast cancer helps in amelioration of the diseased condition.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Middle Aged; Molybdenum; Postmenopause; Riboflavin; Tamoxifen; Xanthine Oxidase

The increase in serum uric acid induced by cytostatic drugs may be treated by a combined low-dose uricostatic and uricosuric regimen. The results obtained in an intraindividual cross-over study demonstrate the significant influence on serum uric acid and its renal excretion.

Topics: Adenocarcinoma; Adult; Aged; Allopurinol; Antineoplastic Agents; Breast Neoplasms; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Lymphoma; Middle Aged; Multiple Myeloma; Sarcoma; Uric Acid

The breast cancer resistance protein (BCRP) is a key drug transporter found in the liver, kidney, central nervous system, and gastrointestinal tract. Due to the wide expression of BCRP, interactions of other drugs with methotrexate (MTX) may differ in oral and intravenous MTX users, and understanding of these interactions may be useful in preventing severe adverse events. Febuxostat, a urate-lowering drug, inhibits BCRP.. The objective of this study was to clarify the differences in the drug-drug interaction profiles of oral and intravenous methotrexate, associated with BCRP.. We analyzed the Japanese Adverse Drug Event Report database and compared the frequency of hematologic events in patients taking oral and intravenous MTX, with or without the concomitant use of febuxostat or allopurinol. Hematologic events were defined as pancytopenia and neutropenia. Multiple logistic regression analysis was then used to identify the risk factors for hematologic events in oral and intravenous MTX users.. We identified 8 453 oral and 810 intravenous MTX users with 546 and 126 cases of hematologic events, respectively. Compared with those not using febuxostat, a disproportionate number of hematologic events was observed in intravenous MTX users concomitantly using febuxostat (. Our findings suggest that patients being treated with intravenous MTX who concomitantly use febuxostat may be at an increased risk of hematologic events, presumably due to BCRP-mediated drug-drug interaction.

Topics: Allopurinol; ATP Binding Cassette Transporter, Subfamily G, Member 2; Breast Neoplasms; Febuxostat; Female; Gout Suppressants; Humans; Methotrexate; Middle Aged; Neoplasm Proteins

In this study, a series of B-ring fluoro substituted bis-chalcone derivatives were synthesized by Claisen-Schmidt condensation reactions and evaluated for their ability to inhibit xanthine oxidase (XO) and growth inhibitory activity against MCF-7 and Caco-2 human cancer cell lines, in vitro. According to the results obtained, the bis-chalcone with fluoro group at the 2 (4b) or 2,5-position (4g) of B-ring were found to be potent inhibitors of the enzyme with IC

Topics: Antineoplastic Agents; Breast Neoplasms; Catalytic Domain; Cell Proliferation; Cell Survival; Chalcone; Enzyme Inhibitors; Female; Humans; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship; Tumor Cells, Cultured; Xanthine Oxidase

MICA/B (the major histocompatibility antigen-related chain A and B) and Rae I are stress-inducible ligands for the immune-receptor NKG2D. Mechanisms by which genotoxic stress and DNA damage induce the expression of NKG2D ligands remain incompletely understood. Here, we report that inhibition of xanthine oxidoreductase (XOR) activity by allopurinol or inhibition of XOR expression by gene knockdown abrogated genotoxic stress-induced expression of MICA/B and Rae I in three tumor cell lines. XOR knockdown also blocked gemcitabine-mediated antitumor activity in an orthotopic syngeneic mouse model of breast cancer. As a rate-limiting enzyme in the purine catabolic pathway, XOR generates two end-products, uric acid and reactive oxygen species (ROS). ROS scavenging had an insignificant effect on genotoxic drug-induced MICA/B expression but modestly inhibited radiation-induced MICA/B expression. Exogenous uric acid (in the form of monosodium urate) induced MICA/B expression by activating the MAP kinase pathway. Allopurinol blocked genotoxic stress-induced MAP kinase activation. Our study provides mechanistic insights into genotoxic stress-induced activation of the MAP kinase pathway and suggests that XOR is required for genotoxic stress-induced NKG2D ligand expression and gemcitabine-mediated antitumor activity.

Topics: Allopurinol; Animals; Breast Neoplasms; Cell Line, Tumor; DNA Damage; Female; Gene Expression Regulation, Neoplastic; Histocompatibility Antigens Class I; Humans; Killer Cells, Natural; MAP Kinase Signaling System; Mice; NK Cell Lectin-Like Receptor Subfamily K; Nuclear Matrix-Associated Proteins; Nucleocytoplasmic Transport Proteins; RNA, Small Interfering; Xanthine Dehydrogenase; Xenograft Model Antitumor Assays

Metabolomics analysis was used to determine the effect of two well known, non-proprietary metabolic modulators, dichloroacetate and allopurinol on breast cancer cell lines. Dichloroacetate, a pyruvate dehydrogenase kinase inhibitor and allopurinol, a xanthine oxidase/dehydrogenase inhibitor, have been previously explored as chemotherapeutics showing potential in some cancer subtypes while at the same time leading to unexpected increase in proliferation in others. In this work, metabolic effects of these drugs, applied singly and in combination, were explored in three different breast cell lines including cancer cells, MDA-MB-231 and MCF-7 and normal control cell line, MCF-10A. The metabolic changes induced by these drugs were monitored by (1)H NMR metabolic profiling. Analyses were performed on complete spectral data as well as quantified metabolic data in intracellular fractions and extracellular media leading to the determination of the most significantly affected metabolites. The effect of dichloroacetate and allopurinol is the most apparent in the metabolic profile of extracellular media. In MCF-7 cells, dichloroacetate treatment is dominant with only a minor observed influence of allopurinol in combined treatment. In MDA-MB-231 cells, both allopurinol and DCA lead to a metabolic shift with the allopurinol change dominating the effect of combined treatment. Results show the power of metabolomics as a tool for fast molecular profiling of drug effects in cells. In summary, treatments of breast cancer cells with DCA and allopurinol result in larger changes in metabolites found in extracellular medium than intracellular pools.

Topics: Allopurinol; Breast Neoplasms; Cell Line, Tumor; Dichloroacetic Acid; Enzyme Inhibitors; Female; Humans; MCF-7 Cells; Metabolomics; Proton Magnetic Resonance Spectroscopy

Oxidative stress has been associated with a wide range of diseases including atherosclerosis, cancer and Alzheimer's disease. When present in excessive concentrations, reactive oxygen species (ROS) can cause deleterious effects. This has led to the notion that the anticancer effects of various chemotherapeutics may be mediated, at least in part, by an increase in ROS. To investigate the role of xanthine oxidase (XO), a source of hydrogen peroxide, in cell death, MCF7, HeLa and 293T cells were treated with various cell-death-inducing drugs in the presence and absence of allopurinol, a specific inhibitor of XO. In the absence of allopurinol, each drug led to a time- and concentration-dependent increase in percent DNA fragmentation and ROS levels, regardless of the mechanism of cell death incurred, i.e. caspase dependent and caspase independent. By contrast, pretreatment with allopurinol led to dramatically lower ROS levels in all cases, suggesting that XO is a major contributor to oxidative stress. However, allopurinol did not exhibit a protective effect against cell death. Similarly, the administration of siRNA against XO also did not exhibit a protective effect against cell death. The level of oxidative stress was recorded using the ROS sensor CM-H(2) DCFDA and a ratiometric bioluminescent assay that takes advantage of the increased sensitivity of Firefly luciferase to hydrogen peroxide, compared with a stable variant of Renilla luciferase (RLuc), RLuc8. Overall, these findings suggest that XO-generated hydrogen peroxide, and perhaps hydrogen peroxide in general, is a consequence, but not a mediator of cell death.

Topics: Allopurinol; Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Doxorubicin; Female; Free Radical Scavengers; HeLa Cells; Humans; Hydrogen Peroxide; In Situ Nick-End Labeling; Luciferases, Firefly; Luminescent Measurements; Mice; Mice, Nude; Mutation; Oxidants; Oxidative Stress; Plasmids; Reactive Oxygen Species; RNA, Small Interfering; Xanthine Oxidase; Xanthines

Mitochondria and associated oxidative stress have been shown to play critical roles in apoptotic death induced by various stress agents. Previously, we reported the antitumor property of diospyrin (D1), a plant-derived bisnaphthoquinonoid, and its diethylether derivative (D7), which was found to cause apoptotic death in human cancer cell lines. The present study aims to explore the relevant mechanism of apoptosis involving generation of cellular reactive oxygen species (ROS) by D7 in human breast carcinoma (MCF-7) cells. It was found that while D7 inhibited the proliferation of tumor cells, the associated apoptosis induced by D7 was prevented by treating the cells with N-acetyl-L-cysteine (NAC), an antioxidant, and cyclosporine A (CsA), an inhibitor of mitochondrial permeability transition (MPT). Experiments using suitable inhibitors also demonstrated that D7 could alter the electron flow in mitochondrial electron transport chain by affecting target(s) between complex I and complex III, and indicated the probable site of D7-induced generation of ROS. These results were further supported by confocal microscopic observation on changes in mitochondrial organization and shape in cells treated with D7. Taken together, the results of our study clearly suggested that the apoptosis induced by D7 would involve alteration of MPT, cardiolipin peroxidation, migration of Bax from cytosol to mitochondria, decreased expression of Bcl-2, and release of cytochrome c, indicating oxidative mechanism at the mitochondrial level in the tumor cells.

Topics: Acetylcysteine; Allopurinol; Animals; Antimycin A; Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Cardiolipins; Cell Line, Tumor; Cyclosporine; Cytochromes c; Female; Free Radical Scavengers; Humans; Membrane Potential, Mitochondrial; Mitochondria; Naphthoquinones; Oxidation-Reduction; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Rotenone; Uncoupling Agents; Vitamin K 3

Recent studies from our laboratory provided evidence that part of the carcinogenic effects of ethanol consumption might be related to its in situ metabolism at cytosolic and microsomal levels, to the mutagen acetaldehyde and to hydroxyl and 1-hydroxyethyl radicals. In this work, we report on our experiments where Sprague-Dawley female rats were exposed to the standard Lieber & De Carli diet for 28 days. We observed: the induction of the (xanthineoxidoreductase mediated) cytosolic and microsomal (lipoxygenase mediated) pathways of ethanol metabolism; promotion of oxidative stress as shown by increased formation of lipid hydroperoxides; delay in the t-butylhydroperoxide induced chemiluminiscence, and a significant decrease in protein sulfhydryls. In addition, the epithelial cells showed ultrastructural alterations consisting of markedly irregular nuclei, with frequent invaginations at the level of the nuclear envelope, condensation of chromatin around the inner nuclear membrane, and marked dilatation of the nuclear pores showing filamentous material exiting to the cytoplasm. In conclusion, the presence in mammary epithelial cells of cytosolic and microsomal pathways of ethanol bioactivation to carcinogenic and to tumorigenic metabolites might play a role in alcohol promotion of breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetaldehyde; Alcohol Drinking; Animals; Breast Neoplasms; Central Nervous System Depressants; Cytosol; Deoxyguanosine; Diet; Ethanol; Female; Fluorescent Dyes; Free Radicals; Humans; Immunohistochemistry; Mammary Glands, Animal; Microscopy, Electron, Transmission; Microsomes; Oxidative Stress; Phenols; Rats; Rats, Sprague-Dawley; Sulfhydryl Compounds; Sulfoxides; Xanthine Oxidase; Xylenes

There is a well-established association between alcohol consumption and breast cancer risk. About 4% of the breast cancers in developed countries are estimated to be attributable to drinking alcohol. The mechanism of tumor promotion by alcohol remains unknown. Recent studies from our laboratory and others showed the ability of mammary tissue to bioactivate ethanol to mutagenic/carcinogenic acetaldehyde and free radicals. Xanthine oxidoreductase (XOR) is an enzyme involved in those biotransformation processes. In the present study, we provide evidence of the ability of different natural polyphenols and of folic acid derivatives to inhibit the biotransformation of alcohol to acetaldehyde by rat breast cytosolic XOR. Folic acid and dihydrofolic acid, at concentrations of 10 microM, inhibited 100% and 84%, respectively, of the cytosolic acetaldehyde formation. Thirty-five polyphenols were tested in these initial experiments: ellagic acid, myricetin, quercetin, luteolin, and apigenin inhibited 79-95% at 10 microM concentrations. The remaining polyphenols were either less potent or noninhibitory of acetaldehyde formation at similar concentrations in these screening tests. Results are relevant to the known preventive effects of folic acid against alcohol-induced breast cancer and to their potential preventive actions if added to foods or alcoholic beverages.

Topics: Acetaldehyde; Alcohol Drinking; Animals; Biotransformation; Breast; Breast Neoplasms; Cytosol; Ethanol; Female; Flavonoids; Folic Acid; Free Radicals; Phenols; Polyphenols; Rats; Rats, Sprague-Dawley; Xanthine Oxidase

The ability to sensitize cancer cells to radiation would be highly beneficial for successful cancer treatment. One mode of action for ionizing radiation is the induction of cell death through infliction of extensive oxidative damage to cellular DNA, including mitochondrial DNA (mtDNA). The ability of cells to repair mtDNA and otherwise maintain the integrity of their mitochondria is vital for protection of the cells against oxidative damage. Because efficient repair of oxidative damage in mtDNA may play a crucial role in cancer cell resistance, interference with this repair process could be an effective way to achieve a radiation sensitive phenotype in otherwise resistant cancer cells. Successful repair of DNA is achieved through a precise and highly regulated multistep process. Expression of excessive amounts of one of the repair enzymes may cause an imbalance of the whole repair system and lead to the loss of repair efficiency. To study the effects of changing mtDNA repair capacity on overall cell survival following oxidative stress, we expressed a bacterial repair enzyme, Exonuclease III (ExoIII) containing the mitochondrial targeting signal of manganese superoxide dismutase, in a human malignant breast epithelial cell line, MDA-MB-231. Following transfection, specific exonuclease activity was found in mitochondrial extracts. In order to examine the effects on repair of oxidative damage in mtDNA, cells were exposed to the enzyme xanthine oxidase and its substrate hypoxanthine. mtDNA repair was evaluated using quantitative Southern blot analysis. The results revealed that cells expressing ExoIII in mitochondria are deficient in mtDNA repair when compared with control cells that express ExoIII without MTS. This diminished mtDNA repair capacity rendered MDA-MB-231 cells more sensitive to oxidative damage, which resulted in a decrease in their long-term survival following oxidative stress.

Topics: Blotting, Southern; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Survival; DNA Repair; DNA, Mitochondrial; Dose-Response Relationship, Drug; Escherichia coli; Exodeoxyribonucleases; Humans; Mitochondria; Oxidative Stress; Phenotype; Polymerase Chain Reaction; Radiation, Ionizing; Reactive Oxygen Species; Spectrophotometry; Subcellular Fractions; Time Factors; Transfection; Xanthine Oxidase

Epidemiological evidence links alcohol intake with increased risk in breast cancer. Not all the characteristics of the correlation can be explained in terms of changes in hormonal factors. In this work, we explore the possibility that alcohol were activated to acetaldehyde and free radicals in situ by xanthine dehydrogenase (XDh) and xanthine oxidase (XO) and/or aldehyde oxidase (AO). Incubation of cytosolic fraction with xanthine oxidoreductase (XDh+XO) (XOR) cosubstrates (e.g. NAD+, hypoxanthine, xanthine, caffeine, theobromine, theophylline or 1,7-dimethylxanthine) significantly enhanced the biotransformation of ethanol to acetaldehyde. The process was inhibited by allopurinol and not by pyrazole or benzoate or desferrioxamine and was not accompanied by detectable formation of 1HEt. However, hydroxylated aromatic derivatives of PBN were detected, suggesting either that hydroxyl free radicals might be formed or that XOR might catalyze aromatic hydroxylation of PBN. No bioactivation of ethanol to acetaldehyde was detectable when a cosubstrate of AO such as N-methylnicotinamide was included in cytosolic incubation mixtures. Results suggest that bioactivation of ethanol in situ to a carcinogen, such as acetaldehyde, and potentially to free radicals, might be involved in alcohol breast cancer induction. This might be the case, particularly also in cases of a high consumption of purine-rich food (e.g. meat) or beverages or soft drinks containing caffeine.

Topics: Acetaldehyde; Alcohol Drinking; Animals; Animals, Outbred Strains; Biotransformation; Breast; Breast Neoplasms; Cytosol; Ethanol; Female; Free Radicals; Humans; Rats; Rats, Sprague-Dawley; Xanthine Dehydrogenase; Xanthine Oxidase

The enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) expressed by the parasite Trypanosoma brucei (Tb) can convert allopurinol, a purine analogue, to corresponding nucleotides with greater efficiency than its human homologue. We have developed a retroviral system that expresses the parasitic enzyme and tested its capacity to activate the prodrug allopurinol to a cytotoxic metabolite. Cytotoxicity assays demonstrated that five non-small cell lung carcinoma cell lines transduced with the construct were sensitized to the prodrug by 2.1- to 7.6-fold compared with control values. This selectivity was not observed in seven other cell lines also expressing the construct, such as breast carcinoma. Assays indicated that enhanced cytotoxicity to allopurinol correlated with induction of apoptosis in lung cancer cells. The selectivity of this suicide gene was not explained either by the TbHGPRT expression or by the allopurinol accumulation. Our study shows that this novel system may represent a therapeutic tool for gene prodrug targeting of lung cancer, considering the fact that allopurinol is well tolerated in humans.

Topics: Allopurinol; Animals; Apoptosis; Blotting, Western; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Genes, Lethal; Genes, Protozoan; Genetic Therapy; Humans; Hypoxanthine Phosphoribosyltransferase; Lung Neoplasms; Microscopy, Fluorescence; Organ Specificity; Prodrugs; Time Factors; Transduction, Genetic; Trypanosoma brucei brucei; Tumor Cells, Cultured; Vesicular stomatitis Indiana virus

Topics: Administration, Intravaginal; Aged; Allopurinol; Antimetabolites; Antineoplastic Agents; Breast Neoplasms; Female; Humans; Vaginitis

In attempts to increase fluorouracil (FU) activity by pharmacomodulation, most attention has been paid to FU activation pathways without consideration of the presence and possible role of FU catabolism in the target tumoral cell itself. The first step in the catabolism of FU is hydrogenation by the enzyme dihydropyrimidine dehydrogenase (DPD). The purpose of the present study was to test the DPD-inhibitory effects of several agents whose use as FU biomodulators has been clinically established: cisplatin, hydroxyurea, dipyridamole, and allopurino. Five cancer cell lines of human origin were used. Dipyridamole and hydroxyurea were the only modulators for which an augmentation in FU cell-growth inhibition (MTT test) was clearly evident for the whole panel of cell lines investigated (P<1.10(-4) and P=0.005, respectively). With dipyridamole the efficacy of FU was multiplied by a factor of around 5. Allopurinol and cisplatin had no obvious effect on cellular DPD activity (biochemical method). For dipyridomole and hydroxyurea, DPD activity showed a more or less marked concentration-related inhibition according to the cell line tested. Only dipyridamole produced reductions in FU IC50 values (50% growth-inhibitory concentrations), i.e., potentiation of FU cytotoxicity, that were significantly related to inhibition of cellular DPD activity. This DPD-mediated interaction between dipyridamole and FU is a new finding that could be important for a better understanding of FU-dipyridamole combination chemotherapy.

Topics: Allopurinol; Antimetabolites, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Carcinoma; Cell Division; Cisplatin; Dihydrouracil Dehydrogenase (NADP); Dipyridamole; Dose-Response Relationship, Drug; Drug Interactions; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Hydroxyurea; Oxidoreductases; Pancreatic Neoplasms; Platelet Aggregation Inhibitors; Tumor Cells, Cultured

Topics: Allopurinol; Breast Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Mouthwashes; Stomatitis

Topics: Adenocarcinoma; Allopurinol; Antineoplastic Agents; Breast Neoplasms; Bronchial Neoplasms; Female; Gout; Humans; Kidney Neoplasms; Lymphoma; Plasmacytoma; Sarcoma; Uric Acid

This study comprises 46 patients with various stages of breast carcinoma and 49 normal women as control group. Serum xanthine oxidase and uric acid levels were determined. Assessment in terms of changes of the enzyme xanthine oxidase was carried out prior and after surgery as a short term follow up. There was a significant fall of serum xanthine oxidase in patients with breast carcinoma. The level of serum xanthine oxidase was found to be varied with the stage of cancer.

Topics: Adult; Aged; Breast Neoplasms; Female; Humans; Middle Aged; NAD; Neoplasm Staging; Time Factors; Uric Acid; Xanthine Oxidase; Xanthines

Topics: Allopurinol; Blood Platelets; Blood Transfusion; Breast Neoplasms; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Leukopenia; Middle Aged; Patient Isolation; Thrombocytopenia; Uric Acid

Topics: Adult; Breast Neoplasms; Female; Humans; Middle Aged; Uric Acid; Xanthine Oxidase

Topics: Adolescent; Age Factors; Allopurinol; Ampicillin; Autopsy; Blood Protein Electrophoresis; Bone Marrow; Breast; Breast Neoplasms; Cyclophosphamide; Female; gamma-Globulins; Glucocorticoids; Hemoglobinometry; Humans; Leukocyte Count; Multiple Myeloma; Ovary; Uterus; Vincristine

Topics: Acute Kidney Injury; Adult; Aged; Allopurinol; Breast Neoplasms; Carcinoma; Emergencies; Estradiol; Female; Humans; Hypercalcemia; Male; Neoplasm Metastasis; Neoplasms; Uric Acid

Topics: Animals; Breast; Breast Neoplasms; Humans; Mammary Neoplasms, Animal; Neoplasms; Oxidoreductases; Xanthine Oxidase