allopurinol and Adenocarcinoma

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

Thirty patients with a diagnosis of metastatic adenocarcinoma of the lung were entered on a trial to evaluate the antitumor efficacy of 5-fluorouracil 370 mg/m2 daily for 5 days every four weeks in combination with folinic acid 200 mg/m2, 60 min prior to 5FU. All patients had a good performance status, bidimensionally measurable disease, and weight loss less than or equal to 5% of preillness weight. Of the 29 evaluable patients, only two (7%) had partial responses (95% confidence limits 1-24%). Eleven (38%) had stable disease and 16 (55%) progressed. The two responding patients survived 12 and 60+ weeks. The median survival of all evaluable patients was 25 weeks (range 7-60+) and that of the stable patients was 26 weeks. The principal toxicities observed were diarrhea and stomatitis. Myelosuppression was rarely dose limiting. In contrast to the results of treatment with 5FU and folinic acid in metastatic colorectal cancer and breast cancer, the results of treatment with this combination of agents have been much less encouraging in adenocarcinoma of the lung.

Topics: Adenocarcinoma; Adult; Aged; Allopurinol; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Fatigue; Female; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Nausea; Nervous System; Stomatitis

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

Oxipurinol, the major metabolite of allopurinol, decreased the toxicity of 5-fluorouracil (5-FU) to human granulocyte colony-forming units in vitro by a factor of four. The ability of allopurinol to reduce 5-FU toxicity in vivo was studied in 23 advanced cancer patients during 42 courses of treatment. 5-FU was administered by continuous intravenous infusion for five days; allopurinol, 300 mg, po, every 8 hours was started 2 hours before and continued during and for 24 hours after 5-FU infusion. 5-FU was escalated from 1.5 to 2.25 g/m2/day on separate courses; the dose-limiting toxicity was mucositis which occurred at a level of 2.0 g/m2/day. At a 5-FU dose rate of greater than 2.0 g/m2/day 5-FU pharmacokinetics were nonlinear, reflecting saturation of catabolic pathways, and the steady-state 5-FU serum concentration was approximately 4 times that which was tolerable without allopurinol. At these concentrations of 5-FU oxipurinol significantly influenced the clearance of 5-FU. Thus concurrent allopurinol therapy permitted a doubling of the maximum tolerated dose of 5-FU and a four-fold increase in the tolerated concentration x time exposure to 5-FU.

Topics: Adenocarcinoma; Allopurinol; Clinical Trials as Topic; Dose-Response Relationship, Drug; Fluorouracil; Gastrointestinal Neoplasms; Humans; Kinetics; Oxypurinol

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

Cancer cachexia is a wasting condition, driven by systemic inflammation and oxidative stress. This study investigated eicosapentaenoic acid (EPA) in combination with oxypurinol as a treatment in a mouse model of cancer cachexia. Mice with cancer cachexia were randomized into 4 treatment groups (EPA (0.4 g/kg/day), oxypurinol (1 mmol/L ad-lib), combination, or control), and euthanized after 29 days. Analysis of oxidative damage to DNA, mRNA analysis of pro-oxidant, antioxidant and proteolytic pathway components, along with enzyme activity of pro- and antioxidants were completed on gastrocnemius muscle. The control group displayed earlier onset of tumor compared to EPA and oxypurinol groups (P<0.001). The EPA group maintained body weight for an extended duration (20 days) compared to the oxypurinol (5 days) and combination (8 days) groups (P<0.05). EPA (18.2±3.2 pg/ml) and combination (18.4±3.7 pg/ml) groups had significantly higher 8-OH-dG levels than the control group (12.9±1.4 pg/ml, P≤0.05) indicating increased oxidative damage to DNA. mRNA levels of GPx1, MURF1 and MAFbx were higher following EPA treatment compared to control (P≤0.05). Whereas oxypurinol was associated with higher GPx1, MnSOD, CAT, XDH, MURF1, MAFbx and UbB mRNA compared to control (P≤0.05). Activity of total SOD was higher in the oxypurinol group (32.2±1.5 U/ml) compared to control (27.0±1.3 U/ml, P<0.01), GPx activity was lower in the EPA group (8.76±2.0 U/ml) compared to control (14.0±1.9 U/ml, P<0.05), and catalase activity was lower in the combination group (14.4±2.8 U/ml) compared to control (20.9±2.0 U/ml, P<0.01). There was no change in XO activity. The increased rate of weight decline in mice treated with oxypurinol indicates that XO may play a protective role during the progression of cancer cachexia, and its inhibition is detrimental to outcomes. In combination with EPA, there was little significant improvement from control, indicating oxypurinol is unlikely to be a viable treatment compound in cancer cachexia.

Topics: Adenocarcinoma; Animals; Cachexia; Catalase; Cell Line, Tumor; Drug Evaluation, Preclinical; Drug Therapy, Combination; Eicosapentaenoic Acid; Enzyme Inhibitors; Female; Gene Expression; Mice; Mice, Inbred BALB C; Mice, Nude; Muscle, Skeletal; Muscular Atrophy; Neoplasm Transplantation; Neoplasms, Experimental; Organ Size; Oxidative Stress; Oxypurinol; Superoxide Dismutase; Tumor Burden; Weight Loss; Xanthine Oxidase

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

Xanthine oxidoreductase (XOR) is a key enzyme in the degradation of DNA, RNA and high-energy phosphates. About half of the patients with breast cancer have a decrease in XOR expression. Patients with breast cancer with unfavourable prognosis are independently identified by the loss of XOR.. To assess the clinical relevance of XOR expression in gastric cancer.. XOR levels were studied by immunohistochemistry in tissue microarray specimens of 337 patients with gastric cancer and the relation between XOR expression and a series of clinicopathological variables, as well as disease-specific survival, was assessed.. XOR was moderately decreased in 41% and was undetectable in another 14% of the tumours compared with the corresponding normal tissue. Decreased XOR was associated with advanced stage, deep tumour penetration, diffusely spread tumour location, positive lymph node status, large tumour size, non-curative disease, cellular aneuploidy, high S-phase fraction and high cyclooxygenase-2 expression, but not with p53 expression or Borrmann classification. Down regulation of XOR was associated with unfavourable outcome, and the cumulative 5-year gastric cancer-specific survival in patients with strong XOR expression was 47%, compared with 22% in those with moderate to negative expression (p<0.001). This was also true in patients with stage I-II (p = 0.01) and lymph node-negative (p = 0.02) disease, as well as in patients with smaller (< or =5 cm) tumours (p = 0.02).. XOR expression in gastric cancer may be a new marker for a more aggressive gastric cancer biology, similar to that previously reported for breast cancer.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; Cytoplasm; Female; Follow-Up Studies; Gastric Mucosa; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Protein Array Analysis; Stomach Neoplasms; Survival Analysis; 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

The extracellular matrix (ECM) facilitates pancreatic cancer cells survival, which is of central importance for pancreatic adenocarcinoma that is highly fibrotic. Here, we show that reactive oxygen species (ROS) mediate the prosurvival effect of ECM in human pancreatic cancer cells. Fibronectin and laminin stimulated ROS production and NADPH oxidase activation in pancreatic cancer cells. Both pharmacological and molecular approaches show that fibronectin stimulated ROS production through activation of NADPH oxidase and NADPH oxidase-independent pathways and that 5-lipoxygenase (5-LO) mediates both these pathways. Analyses of the mechanisms of ROS production by ECM proteins and growth factors indicate that activation of NADPH oxidase (Nox4) is a common mechanism employed both by ECM proteins and growth factors to increase ROS in pancreatic cancer cells. We also found that Nox4 is present in human pancreatic adenocarcinoma tissues and that these tissues display membrane NADPH oxidase activity. ECM proteins and growth factors activate NADPH oxidase through different mechanisms; in contrast to ECM proteins, growth factors activate NADPH oxidase through 5-LO-independent mechanisms. Inhibition of 5-LO or NADPH oxidase with pharmacological inhibitors of these enzymes and with Nox4 or 5-LO antisense oligonucleotides markedly stimulated apoptosis in cancer cells cultured on fibronectin. Our results indicate that ROS generation via 5-LO and downstream NADPH oxidase mediates the prosurvival effect of ECM in pancreatic cancer cells. These mechanisms may play an important role in pancreatic cancer resistance to treatments and thus represent novel therapeutic targets.

Topics: Adenocarcinoma; Antioxidants; Apoptosis; Arachidonate 5-Lipoxygenase; Cell Line, Tumor; Cell Survival; Collagen Type I; Extracellular Matrix; Fibronectins; Humans; Laminin; Lipoxygenase Inhibitors; NADPH Oxidase 4; NADPH Oxidases; Nitric Oxide Synthase; Oligonucleotides, Antisense; Pancreatic Neoplasms; Reactive Oxygen Species; Xanthine Oxidase

Three basic forms of mammalian SODs exist and they are distinguished by their sizes and locations. SOD enzyme activity is not easily monitored by direct measurement because the substrate disappearance is very rapid at physiological pH. Activity can be measured as described in this unit by a number of indirect competitive inhibition assays based on the principle that the superoxide anion radical will reduce an inhibitory substrate [such as nitroblue tetrazolium (NBT) or cytochrome c] and SOD activity will reduce the rate of reduction in a competitive fashion. The SOD-mediated inhibition of the indicator substrate reduction can then be quantitated and plotted as a function of the quantity of protein added to the reaction to construct an inhibition curve.

Topics: Adenocarcinoma; Animals; Copper; Mammals; Mammary Glands, Animal; Manganese; Mitochondria, Liver; Nitroblue Tetrazolium; Phenanthrolines; Rats; Spectrophotometry; Superoxide Dismutase; Xanthine Oxidase; Zinc

Solid tumors induce an angiogenic response by the host blood vessels to form a new vascular network for the supply of fresh nutrients and oxygen responsible for tumor growth. Furthermore, tumor growth and metastatic spread is abrogated or markedly reduced in the absence of neovascularization. Spleen T lymphocytes from tumor-bearing mice elicit a strong neovascular response. It is well known that certain T cell responses require the presence of active oxygen radicals. Because these metabolites are produced during tumor growth, we studied whether oxygen free radicals play a role in the angiogenesis induction by lymphocytes. In this study, we demonstrated that the administration of a free radical scavenger (EGb-761) to tumor-bearing mice, blocked the angiogenic response and decreased the lung metastatic incidence. On the other hand, when normal lymphocytes were incubated with the xanthine-xanthine oxidase system (X-XO), a known superoxide anion generator, this elicited a dose-response positive angiogenic reaction in normal recipient mice. No angiogenic response was observed in the absence of X-XO, or when EGb-761 or superoxide dismutase (SOD) plus catalase (CAT) were added to the incubation medium. These results suggest that free radicals are involved in some step of the angiogenic process, and that the EGb-761 treatments block this response due to the free radical scavenging activity of this compound.

Topics: Adenocarcinoma; Animals; Catalase; Free Radical Scavengers; Ginkgo biloba; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neovascularization, Pathologic; Plant Extracts; Spleen; Superoxide Dismutase; T-Lymphocytes; Xanthine; Xanthine Oxidase; Xanthines

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

Selected immunotherapies (tumor necrosis factor, interleukin-1, interleukin-2, and gamma interferon), chemotherapeutic agents (mitomycin, platinum, doxorubicin [Adriamycin], and bleomycin), and radiation therapy have been described to exert cytotoxicity through the generation of reactive oxygen species, including superoxide and hydrogen peroxide. Tumor necrosis factor, however, has been shown to impart increased resistance in vitro and in vivo against reactive oxygen species stress, including radiation therapy and oxygen toxicity, possibly because of the induction of increased cellular buffering capacities. It is unknown whether the sensitivity of a lung cancer cell to reactive oxygen species therapy is altered by tumor necrosis factor through the induction of free radical scavenging enzymes such as manganese superoxide dismutase. This question was investigated as follows: A549 lung adenocarcinoma cells, exposed for 24 hours to 0, 0.1, 1.0, or 10 micrograms/ml concentrations of tumor necrosis factor, were exposed to hypoxanthine plus xanthine oxidase, a superoxide generating system, for varying intervals. The number of cells surviving 5 days after the stress was determined, and cells exposed to tumor necrosis factor were examined by Northern Blot analysis for induction of the manganese superoxide dismutase gene. The hypoxanthine-xanthine oxidase stress alone caused a time-dependent decrease in survival; however, pretreatment with tumor necrosis factor increased cell survival significantly. Moreover, the cells exposed to tumor necrosis factor had a fivefold increase in the number of manganese superoxide dismutase transcripts. These findings suggest that tumor necrosis factor may confer resistance of lung cancer cells to subsequent reactive oxygen species-based therapies, and the resistance of these cells may be due to increased expression of manganese superoxide dismutase. Clinical treatment failures may result, especially if tumor necrosis factor is given concurrently with other therapies.

Topics: Adenocarcinoma; Cell Division; Enzyme Induction; Humans; Lung Neoplasms; Superoxide Dismutase; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; Xanthine Oxidase

During the course of measuring superoxide dismutase (SOD) activity in rat breast tissue, interferences in the nitroblue tetrazolium (NBT) and cytochrome c assay systems were noted. These interferences inhibit accurate measurement of SOD activity in breast tissues, necessitating the development of a new NBT-based assay that includes compounds capable of inhibiting tissue specific interferences. The most effective compounds were metal chelators that were also electron transport chain inhibitors. Bathocuproine sulfonate (BCS) was the most effective of these compounds. The inclusion of BCS in the NBT assay system was shown to make the accurate measurement of SOD activity in tissues with interferences possible.

Topics: Adenocarcinoma; Animals; Colorimetry; Cytochrome c Group; Female; Iron; Liver; Mammary Glands, Animal; Mice; Mitochondria, Liver; Nitroblue Tetrazolium; Pregnancy; Rats; Rats, Inbred Strains; Superoxide Dismutase; Uric Acid; Vitamin K; Xanthine Oxidase

Topics: Adenocarcinoma; Aged; Allopurinol; Arteritis; Coformycin; Drug Hypersensitivity; Humans; Lung Neoplasms; Male; Necrosis; Pentostatin; Ribonucleosides

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

Antibodies to xanthine oxidase from bovine milk lipid globules localize the antigen in capillary endothelial cells of many tissues including liver, heart, lung and kidney, but not in other epithelial, endothelial or mesenchymal cell types. The antigen from bovine capillaries was purified by immunoaffinity chromatography and shown by chemical, enzymatic and immunological methods to be indistinguishable from milk xanthine oxidase. Using an ultrasensitive radioimmunoassay, concentrations of this protein were found to be 1 000-10 000-fold higher in capillary endothelial cells than in other cells studied except mammary epithelial cells which were also rich in xanthine oxidase. Similar results were obtained with human cells and tissues. In the cytoplasm of capillary endothelial cells, xanthine oxidase was present as a dehydrogenase which was rapidly converted to the O-2-radical-producing oxidase form after release by cell disrupture. This conversion was partly prevented by addition of thiol reagents. Free xanthine oxidase was not detected in human serum, even from patients with extensive capillary lesions. However, specific-apparently constitutive--antibodies (IgG) were present at high concentrations (1-8% of total IgG) in the sera of all individuals tested. A role of these specific antibodies in the removal of the potentially hazardous oxidase form of xanthine oxidase is discussed.

Topics: Adenocarcinoma; Adult; Animals; Antibodies; Capillaries; Cattle; Endothelium; Female; Humans; Male; Milk; Pregnancy; Xanthine Oxidase

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

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

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

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

In an attempt to decrease the activation of 5-FU by normal cells relative to cancer cells, 20 patients with metastatic cancer were given 72 courses of 5-FU and allopurinol (HPP) in a phase I trial. 5-FU was given daily by iv bolus injection for 5 consecutive days every 4 weeks: HPP, 300 mg orally every 8 hours for 6 consecutive days, was started 24 hours before the first injection of 5-FU. HPP appeared to modulate 5-FU toxicity by allowing higher doses (18-21 mg/kg daily for 5 days) to be given. Unexpectedly, neurotoxicity was the dose-limiting toxicity; it was slowly reversible and manifested primarily as encephalopathy, with some patients having cerebellar signs. Gastrointestinal and hematologic toxic effects were mild and infrequent. Because of the high incidence of neurotoxicity and low response rate, this program does not appear to offer any advantages over conventional dose schedules of 5-FU alone.

Topics: Adenocarcinoma; Aged; Allopurinol; Brain Diseases; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Fluorouracil; Gastrointestinal Diseases; Humans; Male; Middle Aged; Neutropenia

Topics: Adenocarcinoma; Amidophosphoribosyltransferase; Animals; Cell Differentiation; Cell Transformation, Neoplastic; Gene Expression Regulation; Humans; Kidney Cortex; Kidney Neoplasms; Kinetics; Neoplasms, Experimental; Pentosyltransferases; Rats; Xanthine Oxidase

Topics: Adenocarcinoma; Adult; Aged; Fanconi Syndrome; Fasting; Female; Humans; Hypoparathyroidism; Kidney; Lung Neoplasms; Male; Middle Aged; Multiple Myeloma; Obesity; Osteomalacia; Uric Acid; Xanthine Oxidase; Xanthines

Topics: Adenocarcinoma; Adult; Allopurinol; Antineoplastic Agents; Calcium; Cyclophosphamide; Fluorouracil; Humans; Hypercalcemia; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Lymphoma; Male; Middle Aged; Neoplasms; Plicamycin; Vincristine