allopurinol and Colonic-Neoplasms

Primary liver tumours and liver metastases from colorectal carcinoma are two of the most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the people with metastatic liver disease will die from metastatic complications. Electrocoagulation by diathermy is a method used to destroy tumour tissue, using a high-frequency electric current generating high temperatures, applied locally with an electrode (needle, blade, or ball). The objective of this method is to destroy the tumour completely, if possible, in a single session. With the time, electrocoagulation by diathermy has been replaced by other techniques, but the evidence is unclear.. To assess the beneficial and harmful effects of electrocoagulation by diathermy, administered alone or with another intervention, versus no intervention, other ablation methods, or systemic treatments in people with liver metastases.. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, CINAHL, ClinicalTrials.gov, ICTRP, and FDA to October 2020.. We considered all randomised trials that assessed beneficial and harmful effects of electrocoagulation by diathermy, administered alone or with another intervention, versus comparators, in people with liver metastases, regardless of the location of the primary tumour.. We used standard methodological procedures expected by Cochrane. We assessed risk of bias of the included trial using predefined risk of bias domains, and presented the review results incorporating the certainty of the evidence using GRADE.. We included one randomised clinical trial with 306 participants (175 males; 131 females) who had undergone resection of the sigmoid colon, and who had five or more visible and palpable hepatic metastases. The diagnosis was confirmed by histological assessment (biopsy) and by carcinoembryonic antigen (CEA) level. The trial was conducted in Iraq. The age of participants ranged between 38 and 79 years. The participants were randomised to four different study groups. The liver metastases were biopsied and treated (only once) in three of the groups: 75 received electrocoagulation by diathermy alone, 76 received electrocoagulation plus allopurinol, 78 received electrocoagulation plus dimethyl sulphoxide. In the fourth intervention group, 77 participants functioning as controls received a vehicle solution of allopurinol 5 mL 4 x a day by mouth; the metastases were left untouched. The status of the liver and lungs was followed by ultrasound investigations, without the use of a contrast agent. Participants were followed for five years. The analyses are based on per-protocol data only analysing 223 participants. We judged the trial to be at high risk of bias. After excluding 'nonevaluable patients', the groups seemed comparable for baseline characteristics. Mortality due to disease spread at five-year follow-up was 98% in the electrocoagulation group (57/58 evaluable people); 87% in the electrocoagulation plus allopurinol group (46/53 evaluable people); 86% in the electrocoagulation plus dimethyl sulphoxide group (49/57 evaluable people); and 100% in the control group (55/55 evaluable people). We observed no difference in mortality between the electrocoagulation alone group versus the control group (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.94 to 1.03; 113 participants; very low-certainty evidence). We observed lower mortality in the electrocoagulation combined with allopurinol or dimethyl sulphoxide group versus the control group (RR 0.87, 95% CI 0.80 to 0.95; 165 participants; low-certainty evidence). We are very uncertain regarding post-operative deaths between the electrocoagulation alone group versus the control group (RR 1.03, 95% CI 0.07 to 16.12; 152 participants; very low-certainty evidence) and between the electrocoagulation combined with allopurinol or dimethyl sulphoxide groups versus the control group (RR 1.00, 95% CI 0.09 to 10.86; 231 participants; very low-certainty evidence). The trial authors did not report data on number of participant. The evidence on the beneficial and harmful effects of electrocoagulation alone or in combination with allopurinol or dimethyl sulphoxide in people with liver metastases is insufficient, as it is based on one randomised clinical trial at low to very low certainty. It is very uncertain if there is a difference in all-cause mortality and post-operative mortality between electrocoagulation alone versus control. It is also uncertain if electrocoagulation in combination with allopurinol or dimethyl sulphoxide may result in a slight reduction of all-cause mortality in comparison with a vehicle solution of allopurinol (control). It is very uncertain if there is a difference in post-operative mortality between the electrocoagulation combined with allopurinol or dimethyl sulphoxide group versus control. Data on other adverse events and complications, failure to clear liver metastases or recurrence of liver metastases, time to progression of liver metastases, tumour response measures, and health-related quality of life were most lacking or insufficiently reported for analysis. Electrocoagulation by diathermy is no longer used in the described way, and this may explain the lack of further trials.

Topics: Adult; Aged; Allopurinol; Cause of Death; Colonic Neoplasms; Dimethyl Sulfoxide; Electrocoagulation; Female; Humans; Liver Neoplasms; Male; Middle Aged; Randomized Controlled Trials as Topic; Solvents

Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the patients with metastatic liver disease will die from metastatic complications. Electro-coagulation is the coagulation (clotting) of tissue using a high-frequency electrical current applied locally with a metal instrument or needle with the aim of stopping bleeding. The object of this technique is to destroy the tumour completely, if possible, in a single surgical session.. To study the beneficial and harmful effects of electro-coagulation compared with no intervention, to other ablation methods, or systemic treatments in patients with liver metastases.. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL up to December 2012.. We included one randomised clinical trial that assessed beneficial and harmful effects of electro-coagulation and its comparators in patients with liver metastases, irrespective of the location of the primary tumour.. We extracted relevant information on participant characteristics, interventions, study outcome measures, and data on the outcome measures as well as information on the design and methodology of the trials. Risk of bias of the trials and data extraction was carried out by one author and checked by a second author.. We included one randomised clinical trial that compared four groups: electro-coagulation alone, electro-coagulation + dimethyl sulphoxide, electro-coagulation + allopurinol, and control (Salim 1993). The risk of bias in the trial is high. In three groups, patients had their metastases destroyed with diathermy electro-coagulation (current set at No 5) and received: 1) solution of allopurinol by mouth 5 mL 4 x a day or 2) allopurinol by mouth 5 mL (50 mg) 4 x a day or 3) dimethyl sulphoxide by mouth 5 mL (500 mg) 4 x a day. In the control group patients received a solution of allopurinol by mouth 5 mL 4 x a day. The treatment was started in the fifth postoperative day and was continued for five years. Three hundred and six patients who had undergone resection of the sigmoid colon and who had five or more hepatic metastases were included; 75 received electro-coagulation alone (58 were evaluable), 76 received electro-coagulation plus allopurinol (53 were evaluable), 78 received electro-coagulation plus dimethyl sulphoxide (57 were evaluable), and 77 were in the control group (55 evaluable).The authors reported the number of deaths due to disease spread (100% in the control, 98% in electro-coagulation, 87% in electro-coagulation + allopurinol, and 86% in the electro-coagulation + dimethyl sulphoxide groups). There was a significant benefit in favour of the electro-coagulation + allopurinol (risk ratio (RR) 0.87 (95% confidence interval (CI) 0.78 to 0.96)) and electro-coagulation + dimethyl sulphoxide (RR 0.86 (95% CI 0.77 to 0.95)) groups compared to the control group, but no such benefit in the electro-coagulation alone group (RR 0.98 (95% CI 0.95 to 1.02)) compared to the control group. There were no local recurrences, no positive tests for occult blood, and observed pulmonary metastases were always with ultrasonographic evidence of hepatic secondaries and were not significantly different for the experimental groups compared to the control group (electro-coagulation: RR 1.11 (95% CI 0.4 to 3.09)), electro-coagulation + allopurinol (RR 0.86 (95% CI 0.28 to 2.66)), electro-coagulation + dimethyl sulphoxide (RR 0.8 (95% CI 0.26 to 2.48)). None of the adverse events were significantly associated with treatment.. On the basis of one randomised trial which did not describe its methodology in sufficient detail to assess risk of bias and quality, excluded 27% of patients after randomisation due to various reasons, and is probably not free from selective outcome reporting bias, there is insufficient evidence to conclude that in patients with colonic cancer liver metastases, electro-coagulation alone brings any significant benefit in terms of survival or recurrence compared with the control. In addition, there is insufficient evidence for the effectiveness of adding allopurinol or dimethyl sulphoxide to electro-coagulation. The probability for selective outcome reporting bias in the trial is high. More randomised trials are needed in order to sufficiently validate electro-coagulation with or without co-interventions.

Topics: Allopurinol; Colonic Neoplasms; Dimethyl Sulfoxide; Electrocoagulation; Humans; Liver Neoplasms; Randomized Controlled Trials as Topic; Solvents

Anti-tumor quinone, including mitomycin C (MMC), needs to be activated by bioreduction to exert its cytotoxic activities. The enzymes underlying this bioreductive activation have been the subject of extensive research on Mitomycin C. Cytochrome P450 reductase, cytochrome b5 reductase, xanthine oxidase, xanthine dehydrogenase and DT-diaphorase (DTD) have been shown to be involved in the reduction of MMC. The relationship between bioreductive enzymes and the cytotoxicity of quinone, however, has not been analyzed yet. In this study, we investigated the relationship between the bioreductive enzymes and the cytotoxicity of MMC. We carried out the following experiments and the following results were obtained. I) We isolated an MMC-resistant variant. This cell showed five-fold resistance to MMC as compared with the parental cell line. DTD was deficient in this resistant cell. II) We have examined the bioreductive enzyme activities of DTD and cytochrome P450 reductase and IC50's of MMC in 13 colon and gastric carcinoma cell lines. A positive correlation was not found between the enzyme activities and MMC sensitivities, but the cells with little or no DTD activity showed higher IC50 values compared to the other cell lines. III) To elucidate directly the role of DTD in MMC sensitivity, we introduced NQO1 gene into St-4 cells. NQO1 gene encodes DTD and St-4 cells have no DTD activity. All of the transfectants showed five- to ten-fold higher sensitivity to MMC as compared to the parental St-4 cells. The above data indicate that DTD is a critical determinant of sensitivity to MMC in aerobic conditions.

Topics: Antibiotics, Antineoplastic; Aziridines; Colonic Neoplasms; Cytochrome Reductases; Cytochrome-B(5) Reductase; Drug Screening Assays, Antitumor; Humans; Indolequinones; Indoles; Mitomycin; Mitomycins; NAD(P)H Dehydrogenase (Quinone); NADH, NADPH Oxidoreductases; NADPH-Ferrihemoprotein Reductase; Stomach Neoplasms; Tumor Cells, Cultured; Xanthine Dehydrogenase; Xanthine Oxidase

Fluorouracil has been the mainstay of chemotherapy in colorectal cancer for many years. We report our experience using fluorouracil in combination with other drugs which may modulate the spectrum of activity. Patients have been treated with allopurinol and fluorouracil and with two schedules of methotrexate and fluorouracil. We discuss other possible approaches to modulate fluorouracil action.

Topics: Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Interactions; Fluorouracil; Humans; Methotrexate; Rectal Neoplasms

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

Gut manipulation during surgery may induce local oxidative stress. Supplemental inspired oxygen increases arterial and tissue oxygen partial pressures. This study examined whether a 0.80 fraction of inspired oxygen (FiO(2)) attenuates the oxidative stress, reducing xanthine oxidase (XO) activity in colonic mucosa as a possible mechanism during colon surgery.. Twenty-four cancer patients who underwent elective colon resection were randomly assigned to either 0.30 FiO(2) or 0.80 FiO(2) during surgery. Malondialdehyde (MDA) and oxidized glutathione (GSSG) levels were measured in blood plasma. We also determined the enzymatic activities of XO and xanthine dehydrogenase (XDH) in the colonic mucosa after resection of the piece of colon.. Oxygen partial pressure in arterial blood was higher in the 0.80 FiO(2) group than in the 0.30 FiO(2) group (P<0.001). MDA and GSSG levels measured in blood plasma as well as MDA measured in colonic mucosa were lower in the 0.80 FiO(2) group than in the 0.30 FiO(2) group. Otherwise, XO enzymatic activity and XO/(XO+XDH) ratio in colonic mucosa were lower in the 0.80 FiO(2) group than in the 0.30 FiO(2) group.. XO may be a major source of reactive oxygen species in patients during colon surgery. Inspiring 0.80 oxygen during colon surgery increases arterial partial pressure and this treatment was associated with reduced XO activity and levels of oxidative stress in colonic mucosa.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Gas Analysis; Colonic Neoplasms; Female; Glutathione Disulfide; Humans; Hyperoxia; Intestinal Mucosa; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Oxygen; Partial Pressure; Reactive Oxygen Species; Xanthine Dehydrogenase; Xanthine Oxidase; Young Adult

The influence of oxygen-derived free radicals on survival in advanced colonic cancer was assessed in a prospective randomized controlled double-blind trial using the radical scavengers dimethyl sulphoxide (DMSO) and allopurinol. Following palliative sigmoid colectomy for carcinoma at Dukes' stage D, 306 patients were randomized to the control group or to electrocoagulation of liver secondaries alone or with allopurinol (50 mg by mouth 4 times a day) or DMSO (500 mg by mouth 4 times a day). In 193 fully evaluable patients who were studied for 5 years, allopurinol and DMSO incurred a significant (p < 0.05) survival advantage over the whole period of study. The similarity in efficacy between allopurinol and DMSO and the fact that the only action they share is scavenging oxyradicals, suggest that these radicals mediate the detrimental effects of malignancy and that removing them incurs a survival advantage for patients with advanced colonic cancer.

Topics: Adenocarcinoma; Adult; Aged; Allopurinol; Analysis of Variance; Colonic Neoplasms; Dimethyl Sulfoxide; Double-Blind Method; Electrocoagulation; Female; Free Radical Scavengers; Humans; Liver Neoplasms; Male; Middle Aged; Proportional Hazards Models; Reactive Oxygen Species; Sigmoid Neoplasms; Survival Rate

Tumour lysis syndrome (TLS) is a rare oncological emergency in solid tumours. Because it is associated with bad short-term prognosis, early recognition and treatment are mandatory. This case refers to a middle-aged woman who presented with stage IV colon cancer, with massive hepatic involvement. After three cycles of first-line FOLFOX (folinic acid, 5-fluorouracil and oxaliplatin), she developed acute kidney injury and hyperkalaemia that did not respond to standard measures. High suspicion of TLS prompted further corroborating investigations and early intensive care unit admission. With vigorous hydration and allopurinol, TLS completely resolved and the patient was discharged. Prophylaxis of subsequent TLS recurrence was complicated by biopsy-proven neutrophilic vasculitis secondary to allopurinol. Prevention of TLS with hydration and rasburicase was performed prior to each subsequent cycle of chemotherapy. This case report is intended to highlight risk factors for TLS in solid tumours and focus on treatment and secondary prophylaxis of TLS.

Topics: Adenocarcinoma; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Diagnosis, Differential; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Organoplatinum Compounds; Palliative Care; Tomography, X-Ray Computed; Tumor Lysis Syndrome

Topics: Adenocarcinoma; Administration, Topical; Allopurinol; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Colonic Neoplasms; Drug Eruptions; Free Radical Scavengers; Humans; Injections, Intravenous; Liver Neoplasms; Male; Middle Aged; Ointments; Treatment Outcome

Tissue injury induces the acute phase response, aimed at minimizing damage and starting the healing process. Polymorphonuclear leukocytes (PMNs) respond to the presence of specific chemoattractants and begin to appear in large numbers. The aim of this study was to investigate the influence of reactive oxygen species (ROS) produced by PMNs on the interaction between colon carcinoma cells and mesothelial cells. An experimental human in vitro model was designed using Caco-2 colon carcinoma cells and primary cultures of mesothelial cells. Tumor cell adhesion to a mesothelial monolayer was assessed after preincubation of the mesothelium with stimulated PMNs and unstimulated PMNs. Mesothelial cells were also incubated with xanthine/xanthine oxidase (X/XO) complex producing ROS after which adhesion of Caco-2 cells was investigated and the expression of adhesion molecules (ICAM-1, VCAM-1, and CD44) by means of enzyme immunoassay. In the control situation the average adhesion of Caco-2 cells to the mesothelial monolayers was 23%. Mesothelial monolayers incubated with unstimulated PMNs showed a 25% increase of tumor cell adhesion (P < 0.05). The adhesion of tumor to the monolayers incubated with the N-formyl-methionyl-leucyl-phenylalanine-stimulated PMNs increased with 40% (P < 0.01). Incubation of the mesothelium with X/XO resulted in an enhancement of adhesion of Caco-2 cells of 70% and an up-regulation of expression of ICAM-1, VCAM-1, and CD44. This study reveals an increase of tumor cell adhesion to the mesothelium induced by incubating the mesothelial monolayers with PMNs. PMNs are producing a number of products, like proteolytic enzymes, cytokines, and ROS. These factors up-regulate the expression of adhesion molecules and in that way stimulate the adhesion of tumor to the mesothelium.

Topics: Acute-Phase Reaction; Caco-2 Cells; Cell Adhesion; Colonic Neoplasms; Cytochromes c; Epithelium; Humans; Immunoenzyme Techniques; In Vitro Techniques; Neoplasm Recurrence, Local; Neutrophils; Reactive Oxygen Species; Reproducibility of Results; Xanthine; Xanthine Oxidase

Effects of extract of dried whole black grape including seed on adenosine deaminase (ADA), 5' nucleotidase (5'NT) and xanthine oxidase (XO) enzymes were investigated in cancerous and non-cancerous human colon tissues. Enzyme activities were measured in 20 colon tissues, 10 from cancerous region and 10 from non cancerous region with and without pre incubation with black grape extract. ADA and 5'NT activities were found increased and that of the XO decreased in the cancerous tissues relative to non cancerous ones. After incubation period with black grape extract for 12 h, ADA and 5'NT activities were found to be significantly lowered but that of XO unchanged in both cancerous and non cancerous tissues. Results suggest that ADA and 5'NT activities increase but XO activity decreases in cancerous human colon tissues, which may provide advantage to the cancerous tissues in obtaining new nucleotides for rapid DNA synthesis through accelerated salvage pathway activity. Black grape extract makes significant inhibition on the ADA and 5'NT activities of cancerous and non cancerous colon tissues, thereby eliminating this advantage of cancer cells, which might be the basis for the beneficial effect of black grape in some kinds of human cancers.

Topics: 5'-Nucleotidase; Adenocarcinoma; Adenosine Deaminase Inhibitors; Colon; Colonic Neoplasms; Fruit; Humans; Plant Extracts; Turkey; Vitis; Xanthine Oxidase

Acute tumor lysis syndrome (ATLS), which occurs spontaneously, without cytotoxic therapy, is a rare condition. Spontaneous TLS (STLS) has been seen most commonly in lymphoma and leukemia. We report a series of 3 cases of STLS in patients with solid tumors who were hospitalized in our department during a 9-month period and suggest that STLS is probably more frequent than previously thought.

Topics: Adrenal Gland Neoplasms; Aged; Aged, 80 and over; Allopurinol; Bone Neoplasms; Colonic Neoplasms; Female; Fluid Therapy; Humans; Hydrogen-Ion Concentration; Liver Neoplasms; Male; Necrosis; Pheochromocytoma; Tomography, X-Ray Computed; Tumor Lysis Syndrome; Urine

The adhesion of colon cancer cells (colo201) and neutrophils to endothelial cells which had been briefly exposed to either hypoxanthine/xanthine oxidase, or hydrogen peroxide, or peroxynitrite was analyzed in the absence of de novo protein synthesis. Such treatments accelerated the adhesions of both colo201 cells and neutrophils to endothelial cells. These effects were blocked by SOD/catalase or EDTA. The results provided evidence that hydroxyl radicals affect the cell surface of endothelial cells and accelerate cell adhesion.

Topics: Catalase; Cell Adhesion; Cell Membrane; Chelating Agents; Colonic Neoplasms; Cycloheximide; Dactinomycin; Edetic Acid; Endothelium, Vascular; Humans; Hydrogen Peroxide; Hydroxyl Radical; Hypoxanthine; Neutrophils; Nitrates; Protein Biosynthesis; Reactive Oxygen Species; Superoxide Dismutase; Tumor Cells, Cultured; Xanthine Oxidase

In our studies to find natural compounds with chemopreventive efficacy in foods, using azoxymethane (AOM)-induced colonic aberrant crypt foci and colonic mucosal cell proliferation as biomarkers, a xanthine oxidase inhibitor, 1'-acetoxychavicol acetate (ACA), present in the edible plant Languas galanga from Thailand was found to be effective. This study was conducted to test the ability of ACA to inhibit AOM-induced colon tumorigenesis when it was fed to rats during the initiation or post-initiation phase. Male F344 rats were given three weekly s.c. injections of AOM (15 mg/kg body weight) to induce colonic neoplasms. They were fed diet containing 100 or 500 ppm ACA for 4 weeks, starting one week before the first dosing of AOM (the initiation feeding). The other groups were fed the ACA diet for 34 weeks, starting one week after the last AOM injection (the post-initiation feeding). At the termination of the study (week 38), AOM had induced 71% incidence of colonic adenocarcinoma (12/17 rats). The initiation feeding with ACA caused significant reduction in the incidence of colon carcinoma (54% inhibition by 100 ppm ACA feeding and 77% inhibition by 500 ppm ACA feeding, P = 0.03 and P = 0.001, respectively). The post-initiation feeding with ACA also suppressed the incidence of colonic carcinoma (45% inhibition by 100 ppm ACA feeding and 93% inhibition by 500 ppm ACA feeding, P = 0.06 and P = 0.00003, respectively). Such inhibition was dose-dependent and was associated with suppression of proliferation biomarkers, such as ornithine decarboxylase activity in the colonic mucosa, and blood and colonic mucosal polyamine contents. ACA also elevated the activities of phase II enzymes, glutathione S-transferase (GST) and quinone reductase (QR), in the liver and colon. These results indicate that ACA could inhibit the development of AOM-induced colon tumorigenesis through its suppression of cell proliferation in the colonic mucosa and its induction of GST and QR. The results confirm our previous finding that ACA feeding effectively suppressed the development of colonic aberrant crypt foci. These findings suggest possible chemopreventive ability of ACA against colon tumorigenesis.

Topics: Animal Feed; Animals; Anticarcinogenic Agents; Azoxymethane; Benzyl Alcohols; Biomarkers, Tumor; Carcinogens; Chemoprevention; Colon; Colonic Neoplasms; Enzyme Inhibitors; Glutathione Transferase; Intestinal Mucosa; Male; NAD(P)H Dehydrogenase (Quinone); Ornithine Decarboxylase; Polyamines; Rats; Rats, Inbred F344; Terpenes; Time Factors; Xanthine Oxidase

In this experimental model, taurine administered during hypoxia markedly reduced the cell damage due to O2 deficiency, and the beneficial effect outlasted the period of reoxygenation. The mechanisms for the improved survival rates are postulated to be a reduced osmoregulatory disturbance of cellular integrity, improved Ca2+ homeostasis and induction of accelerated cellular growth processes. In our simplified cell culture model the UW solution seems to be the most appropriate solution for the cold (hypoxic) preservation of human colon cells. We conclude, that within this experimental model and under these experimental conditions, taurine supplementation of the conventionally used preservation solutions improved the solutions markedly. Considering our previous studies, taurine seems to be a potent endogenous protective agent against cellular deterioration due to hypoxia and reoxygenation.

Topics: Adenosine; Aerobiosis; Allopurinol; Cell Hypoxia; Cell Line; Cell Survival; Colon; Colonic Neoplasms; Glucose; Glutathione; Humans; Hypertonic Solutions; Insulin; Mannitol; Organ Preservation Solutions; Potassium Chloride; Procaine; Raffinose; Taurine; Tissue Preservation

The success of chemotherapy of colon tumours is currently limited. We have therefore used the human colon tumour cell line HT-29 to evaluate the cytotoxic effects of various drug combinations. Trimidox (3,4,5-trihydroxybenzamidoxime), a recently patented inhibitor of ribonucleotide reductase was combined with cytosinearabinoside (Ara-C) or 2',2'-difluorodeoxycytidine (DFDC) in order to inhibit both pyrimidine de novo and salvage pathways. Synergistic cytotoxic effects were observed. When HT-29 cells were sequentially treated with trimidox (20 microM for 24 h) and Ara-C (2 microM for 2 h), colony numbers decreased to 71% of the value calculated for additive cytotoxicity. When cells were simultaneously treated with trimidox (10 microM and 15 microM) and DFDC (0.2 nM), synergistic inhibition of colony formation was likewise noted (colony numbers decreased to values as low as 73% or 71% of the values calculated for additive cytotoxicity). On the other hand, we combined tiazofurin, an inhibitor of the guanylate de novo pathway, with allopurinol, which inhibits the guanylate salvage pathway by increasing intracellular hypoxanthine concentrations, leading to inhibition of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Synergistic cytotoxic effects were observed under these conditions too. When cells were treated with 10 microM tiazofurin and 400 microM or 800 microM allopurinol the number of colonies decreased to 69% and 27%, respectively, of the values calculated for additive effects. Our data suggest these drug combinations to be promising options in the treatment of human colon cancer.

Topics: Allopurinol; Antimetabolites, Antineoplastic; Benzamidines; Cell Line; Cell Survival; Colonic Neoplasms; Cytarabine; Deoxycytidine; Dose-Response Relationship, Drug; Drug Synergism; Gemcitabine; Humans; Hypoxanthine; Hypoxanthines; Ribavirin; Ribonucleotide Reductases; Tumor Cells, Cultured; Tumor Stem Cell Assay

Metastases in rat liver were generated experimentally by intraportal injection of colon cancer cells to investigate the effects of cancerous growth on the metabolism of surrounding liver tissue. Maximum activities (capacity) of glucose-6-phosphate dehydrogenase, phosphogluconate dehydrogenase, lactate dehydrogenase, succinate dehydrogenase, alkaline phosphatase, 5'-nucleotidase, xanthine oxidoreductase, purine nucleoside phosphorylase and adenosine triphosphatase have been determined. Two types of metastases were found, a small type surrounded by stroma and a larger type in direct contact with hepatocytes. Both types affected the adjacent tissue in a similar way suggesting that the interactions were not mediated by stroma. High capacity of the degradation pathway of extracellular purines released from dead cells of either tumours or host tissue was found in stroma and sinusoidal cells. Metastases induced both an increase in the number of Kupffer cells and proliferation of hepatocytes. The distribution pattern in the liver lobulus of most enzymes investigated did not change distinctly. However, activity of alkaline phosphatase, succinate dehydrogenase and phosphogluconate dehydrogenase was increased in hepatocytes directly surrounding metastases. These data imply that the overall metabolic zonation in liver lobuli is not dramatically disturbed by the presence of cancer cells despite the fact that various metabolic processes in liver cells are affected.

Topics: 5'-Nucleotidase; Adenocarcinoma; Adenosine Triphosphatases; Alkaline Phosphatase; Animals; Cell Division; Collagen; Colonic Neoplasms; Glucosephosphate Dehydrogenase; Liver; Liver Glycogen; Liver Neoplasms, Experimental; Oxidoreductases; Purine Nucleotides; Purine-Nucleoside Phosphorylase; Purines; Rats; Rats, Inbred Strains; Xanthine Oxidase

This study examined the influence of the oxygen-derived free radical removing agents allopurinol and dimethyl sulphoxide (DMSO) on the occurrence of hepatic metastases and on the survival rate in the rat with 1,2-dimethylhydrazine (DMH)-induced colonic tumours. At 10 weeks of age, rats were subcutaneously injected every week with 10 mg per kg body weight of DMH for 28 weeks. This produced colonic carcinoma in 80% of animals. The rats that were at this stage continued on their drinking water developed multiple hepatic metastases within 3 months and died at the age of 14.9 +/- 0.3 months (mean +/- SEM). Administration of 1,2 or 5% allopurinol or DMSO for drinking after production of the colonic tumours prevented the development of hepatic metastases 3 months later and significantly (p less than 0.01) extended survival to at least 22.1 +/- 0.1 months of age (mean +/- SEM). The results suggest that in the rat with colonic carcinoma, removing oxyradicals impairs the development of hepatic metastases and prolongs survival.

Topics: 1,2-Dimethylhydrazine; Allopurinol; Animals; Carcinogens; Colonic Neoplasms; Dimethyl Sulfoxide; Dimethylhydrazines; Free Radicals; Liver Neoplasms, Experimental; Male; Oxygen; Rats; Rats, Inbred Strains; Survival Analysis

Topics: Adenoma, Bile Duct; Adenosine; Adult; Allopurinol; Bile Duct Neoplasms; Carcinoma, Hepatocellular; Colonic Neoplasms; Duodenal Neoplasms; Duodenum; Female; Glutathione; Humans; Insulin; Intestine, Small; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Organ Preservation; Organ Preservation Solutions; Pancreas Transplantation; Pancreatic Neoplasms; Raffinose; Solutions

Relationships of reductive potential, kinetics of enzymatic reduction, augmented oxygen consumption, and cytotoxicity were determined for seven clinically relevant mitomycin antibiotics. Potentials for one-electron reduction were obtained by cyclic voltammetry analysis in dimethyl sulfoxide with 0.1 M tetraethyl-ammonium perchlorate. These potentials were -0.55 V for N7-acetylmitomycin C, -0.61 V for mitomycin A, -0.75 V for N7-(p-hydroxyphenyl)mitomycin C, -0.79 V for N7-(dimethylamino-methylene)mitomycin C, -0.81 V for N7-(2-(4-nitrophenyldithio)-ethyl)-mitomycin C, -0.81 V for mitomycin C, and -0.89 V for porfiromycin. All seven antibiotics were reduced by xanthine oxidase and NADPH-cytochrome P450 reductase, but the rate of reduction varied for each antibiotic and each enzyme. The less negative the reductive potential of an antibiotic, the more easily that antibiotic was reduced enzymatically. These seven mitomycin antibiotics also augmented oxygen consumption by rat liver microsomes. As with their reduction by xanthine oxidase and NADPH-cytochrome P450 reductase, the less negative the reductive potential of an antibiotic, the more it augmented oxygen consumption. Cytotoxicity of each antibiotic was assessed by defining the IC50 against HCT 116 human colon carcinoma cells. A relationship between the reductive potential of these antibiotics and their cytotoxicity against HCT 116 cells was also observed.

Topics: Animals; Colonic Neoplasms; Electrochemistry; Humans; Kinetics; Liver; Mitomycin; Mitomycins; NADH Dehydrogenase; Oxidation-Reduction; Oxygen Consumption; Rats; Tumor Cells, Cultured; Xanthine Oxidase

1,2-Dimethylhydrazine-induced large bowel tumors in adult male rats contained significantly lower levels of xanthine oxidase and xanthine dehydrogenase activities when compared to levels in normal intestinal tissue. Xanthine dehydrogenase activity in the blood serum of DMH-treated rats was significantly higher than that of the control animals.

Topics: Animals; Colonic Neoplasms; Dimethylhydrazines; Male; Rats; Xanthine Dehydrogenase; Xanthine Oxidase

The Eastern Cooperative Oncology Group (ECOG) studied 29 patients with advanced measurable colon cancer who were treated with Aminothiadiazole (NSC #4728) 125 mg/m2 intravenously. Allopurinol 300 mg daily was taken by all patients during treatment. Three patients (12%) demonstrated partial responses on this regimen. Hematologic toxicity did not occur. Gastrointestinal toxicity was severe in 16% of patients and consisted primarily of vomiting and diarrhea. No life-threatening toxicity was encountered. A lack of appreciable toxicity together with the few responses seen suggest that further studies at higher dose may be indicated.

Topics: Allopurinol; Antineoplastic Agents; Colonic Neoplasms; Drug Evaluation; Humans; Neoplasm Metastasis; Thiadiazoles

The formation of FdUMP and the inhibition of TS were studied in a subcutaneously growing transplantable rat colon carcinoma and in regenerating rat liver following bolus administration of 5-FU, with or without HPP pretreatment. In tumor, peak levels of FdUMP at 30 min following bolus 5-FU, 100 mg/kg, averaged 4931 +/- 587 pmol/g. Pretreatment with HPP, 50 mg/kg, 24 h and 1 h before 5-FU, reduced the peak FdUMP level to 2085 +/- 387 pmol/g. The inhibition of TS by 5-FU treatment was greater than 95% by 30 min, and after 48 h residual enzyme inhibition averaged 40%. No effect on TS inhibition by 5-FU treatment could be observed as a result of HPP pretreatment. The levels of TStot increased linearly after 5-FU treatment and doubled within 48 h. In regenerating rat liver, neither FdUMP levels nor TS inhibition, studied at 1 h after bolus 5-FU, were affected by HPP pretreatment.

Topics: Adenocarcinoma; Allopurinol; Animals; Colonic Neoplasms; Deoxyuracil Nucleotides; Female; Fluorodeoxyuridylate; Fluorouracil; Liver; Liver Regeneration; Male; Rats; Rats, Inbred Strains; Thymidylate Synthase; Time Factors

Allopurinol has been shown to ameliorate the myelotoxicity of 5-fluorouracil (5-FU) given as an infusion. To study the potential effectiveness of allopurinol in modifying the toxicity of 5-FU given as a bolus, 8 adult patients with metastatic malignancies were given 11 courses of bolus 5-FU with allopurinol. Allopurinol was administered at a dose of 900 mg/day orally beginning a week prior to the 5-FU therapy and continued a week after the last dose of 5-FU was administered. Three patients received a total of 5 courses of 600 mg/m2 of 5-FU via bolus injection for 4 consecutive days every 28 days. Six patients were given 6 courses of 800 mg/m2 of 5-FU via bolus injection in the same schedule. Gastrointestinal toxicity was mild and no significant neurotoxicity was documented. However, severe myelosuppression occurred at the 800 mg/m2 dosage which led to marked leukopenia in 5 of the 6 patient courses and thrombocytopenia in 1. Gram-negative sepsis developed in 3 of the leukopenic patients with 2 resultant deaths. Allopurinol does not appear to allow clinically significant dose escalation of bolus 5-FU given on this schedule.

Topics: Adenocarcinoma; Adult; Allopurinol; Carcinoma, Squamous Cell; Colonic Neoplasms; Drug Administration Schedule; Fluorouracil; Gallbladder Neoplasms; Gastrointestinal Diseases; Hematologic Diseases; Humans; Lung Neoplasms; Neoplasm Metastasis; Rectal Neoplasms

Twenty patients with metastatic colon cancer without prior chemotherapy received 2 g/m2 of 5-fluorouracil (5-FU) infused over 24 h for 5 days preceded by allopurinol 900 mg orally for 1 week and then continued during, and for 1 week after the infusion was completed. Fourteen patients were evaluable for both response and toxicity. One patient (14%) achieved a partial response lasting 2 months. No significant hematologic toxicity was seen but 18 of 19 patients evaluable for toxicity developed mucositis resulting in dose reductions in 3 patients and refusal of a second course by 2 additional patients. 5-FU infusions with allopurinol as used in this regimen appear to offer no therapeutic advantage over a conventional dosing schedule.

Topics: Adult; Aged; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Evaluation; Fluorouracil; Gastric Mucosa; Humans; Inflammation; Infusions, Parenteral; Male; Middle Aged; Neoplasm Metastasis

Allopurinol has been shown to decrease the gastro-intestinal and bone marrow toxicity of 5-fluorouracil. In an attempt to diminish mucositis resulting from 5-fluorouracil administration, whilst not affecting its systemic anti-tumour activity, an allopurinol mouthwash has been used. In six patients who experienced mucositis when treated initially with 5-fluorouracil, the use of an allopurinol mouthwash with subsequent courses resulted in a reduction of oral toxicity.

Topics: Allopurinol; Colonic Neoplasms; Fluorouracil; Humans; Intestinal Mucosa; Mouth Mucosa; Mouthwashes; Rectal Neoplasms; Stomatitis

Hypoxanthine (Hx) and allopurinol (HPP) have been shown experimentally to reduce the conversion of 5-fluorouracil (FUra) to FUMP by orotate phosphoribosyltransferase (OPRTase). This study was designed to elucidate the major pathway by which FU ra was metabolized to ribonucleotides by human colorectal tumors. Consequently, the effect of Hx and HPP on the metabolism of [6-3H]-FUra was examined in 5 human colorectal adenocarcinomas maintained as xenografts in immune-deprived mice. In 2 tumors the formation of ribonucleotides from FUra was depressed by Hx and HPP in combination during the first hour after treatment, while in 3 other lines ribonucleotide concentrations were not reduced. The data suggested that these 5 xenograft lines may be divided into 2 groups: (1) group 1 tumors formed relatively high levels of FUrd and low levels of fluorinated ribonucleotides after the injection of FUra, with no decrease in ribonucleotide concentrations after the administration of Hx and HPP. These tumors possessed high ratios of uridine (Urd) phosphorylase/orotate phosphoribosyltransferase (OPRTase: 7-24) and ribose-1-phosphate (R-1-P)/5-phosphoribosyl-1-pyrophosphate (PRPP;5), and thus appeared to metabolize FUra by the U rd phosphorylase and U rd kinase pathway; (2) group 2 tumors formed low levels of FU rd, higher concentrations of fluorinated ribonucleotides and a reduction in levels of these nucleotides after administration of the purine combination. Group 2 tumors demonstrated a lower enzyme ratio (1-2), higher endogenous levels of PRPP, a lower R-1-P/PRPP ratio (1) and appeared to metabolize FUra predominantly by the activity of OPRTase. Hypoxanthine and HPP, alone or in combination, caused a rapid depletion of PRPP in each tumor line examined. In group 2 tumors this may be responsible for the decreased formation of FUra ribonucleotides observed.

Topics: Adenocarcinoma; Allopurinol; Animals; Colonic Neoplasms; Female; Fluorouracil; Humans; Hypoxanthines; Male; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Neoplasms, Experimental; Orotate Phosphoribosyltransferase; Orotic Acid; Phosphoribosyl Pyrophosphate; Rectal Neoplasms; Ribosemonophosphates; Transplantation, Heterologous; Uridine Phosphorylase

Concurrent administration of allopurinol allows escalation of 5-FU doses in man when 5-FU is given by continuous infusion for 5 days. Forty-nine patients received 81 courses of treatment with 5-FU and allopurinol in phase I and II trials. The dose-limiting toxicity was mucositis; marrow toxicity was mild. Neurotoxicity, possibly related to 5-FU, occurred in eight patients. No responses were seen in 14 evaluable patients with colon cancer, 11 of whom had had prior 5-FU. One patient with Hodgkin's disease had a partial response; one patient with diffuse histiocytic lymphoma had transient disease regression. Although allopurinol does modify the toxicity of 5-FU, permitting dose escalation, it does not increase the therapeutic index in colon cancer. Infusional 5-FU deserves further study in lymphoma.

Topics: Allopurinol; Brain; Colonic Neoplasms; Drug Evaluation; Drug Therapy, Combination; Fluorouracil; Humans

A series of four human colon adenocarcinomas, growing as xenografts in immune-deprived mice, have been used to evaluate the efficacy of 5-FU in combination with two purines, hypoxanthine (Hx) and allopurinol (HPP), which have reduced the toxicity of 5-FU in host mice. Tumor-bearing mice were treated at 7-day intervals with 5-FU administered simultaneously with the protecting agents (Hx and HPP). Two tumor lines (HxVRC5 and HxGC3), insensitive to 5-FU alone, failed to show any response to this combination. In 5-FU-sensitive HxELC2 tumors, the combination of 5-FU with Hx and HPP did not increase the therapeutic index, and in HxHC1 xenografts, antagonism to 5-FU cytotoxicity was observed. Tumor response in relation to the pathways of 5-FU metabolism is discussed.

Topics: Adenocarcinoma; Allopurinol; Animals; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Humans; Hypoxanthine; Hypoxanthines; Male; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Transplantation, Heterologous

HT-29 human colon tumor cells growing as spheroids have been evaluated as a model system for measuring the response of human colon tumor cell to antineoplastic agents. HT-29 cells have been capacity to form spheroids up to 1 mm or more in diameter when grown in spinner culture. The multicellular HT-29 spheroids develop hypoxic centers reflecting the cellular conditions found in human cancer treatment, i.e., nutritionally deficient hypoxic cells that are felt to be a significant source of both radiation and chemotherapy clinical treatment failures. Spheroids of increasing size were radiated and then dispersed into single cells for colony survival assay. Compared with irradiated single cell suspensions, the spheroid cells demonstrated a significant increase in radioresistance. Growing spheroids developed a complex radiation survival curve which was variable with respect to size of the spheroid. The drug 5-Fu was studied to examine in a preliminary fashion its interaction with these resistant cell fractions. In direct cytotoxicity assay, 5-fluorouracil (5-FU) exhibited both cytotoxic and cytostatic effects when the drug was present at a concentration greater than 0.4 microgram/ml. The interaction of 5-FU with x-rays in the HT-29 spheroids was complex and dependent on the type of assay employed (spheroid size versus clonogenicity). The effect of allopurinol, an agent that protects cells from 5-FU toxicity was examined. Allopurinol at a concentration of 100 microgram/ml was found to protect these human colonic carcinoma cells from the cytotoxic effects of 5-FU under conditions resembling those found in vivo. Overall, this HT-29 spheroid system appears to b an interesting model for studying a variety of drug/x-ray interactions in vitro and may prove capable of answering specific questions of preclinical and clinical relevance.

Topics: Allopurinol; Cell Count; Cell Line; Cell Survival; Colonic Neoplasms; Dose-Response Relationship, Radiation; Evaluation Studies as Topic; Fluorouracil; Humans; Methods; Radiation Tolerance; Time Factors

Topics: Allopurinol; Animals; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Humans; Hypoxanthines; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Transplantation, Heterologous

Topics: Allopurinol; Colon; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Humans

We describe an episode of obstructive uropathy produced by xanthine precipitation in the tubules of the kidney of a patient with histiocytic lymphoma during intensive chemotherapy, despite allopurinol therapy. Urinary oxypurine-uric acid ratio suggested a subclinical deficiency of hypoxanthine-guanine phosphoribosyltransferase. Results of an assay of this enzyme confirmed the abnormality. Both parents and three brothers of the patient had normal enzyme activity. The continued importance of adequate hydration for patients who receive allopurinol during initial periods of cancer therapy is emphasized.

Topics: Acute Kidney Injury; Adolescent; Allopurinol; Colonic Neoplasms; Humans; Hypoxanthine Phosphoribosyltransferase; Kidney Tubules; Lymphoma, Large B-Cell, Diffuse; Male; Purines; Xanthines

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Blood; Bone Marrow Diseases; Child, Preschool; Colonic Neoplasms; Enzyme Therapy; Female; Humans; Leukemia; Lymphoma; Male; Middle Aged; Mycosis Fungoides; Polycythemia Vera; Pyrimidines; Sarcoma; Uric Acid; Urinary Calculi; Xanthine Oxidase