5-6-7-8-tetrahydrofolic-acid and Adenocarcinoma

The purpose of the current study is to evaluate the efficacy and complications of concurrent chemoradiotherapy (CCRT) for the treatment of gastric cancer patients after D1/D2 surgery.. Sixty-eight untreated gastric cancer patients (T3/T4 and/or N+) were enrolled. After surgery, they were randomized into two groups: the CCRT group and the single chemotherapy group. Radiotherapy patients were treated according to the Intergroup 0116 guidelines. The chemotherapy consisted of continuously administered 5-fluorouracil (5-FU) and tetrahydrofolic acid (LV). The CCRT began 28 days after the first cycle of chemotherapy, and chemotherapy was given within the first four and last three days during the CCRT period, at a radiation dosage of 45 Gy/25 f, i.e., 1.8 Gy 5 times per week. Two cycles of the same chemotherapy were administrated 1 month after the radiotherapy. Five cycles of 5-FU and LV were applied to CG.. One-, two-, and three-year survival rates were 85.9, 73.4, and 67.7%, respectively, in the CCRT group and 68.0, 50.0, and 44.1%, in the single chemotherapy group (P < 0.05). The corresponding disease-free survival rates were 73.5, 64.7, and 55.8% in the CCRT group and 61.8, 38.2, and 29.4% in the single chemotherapy group (P < 0.05). The major side effects were gastrointestinal reactions and neutrocytopenia. In both the CCRT and single chemotherapy groups, the incidence of these side effects was 73.5% (25/34) and 44.1% (15/34) (P < 0.05) for Grade I and Grade II anorexia, 82.35% (28/34) and 73.5% (25/34) (P > 0.05) for nausea and vomiting, and 70.6% (24/34) and 44.1% (15/34) (P < 0.05) for neutrocytopenia, respectively. The other indices showed no significant differences.. Our findings indicate that CCRT can increase the one-, two-, and three-year total survival rates, as well as the disease-free survival rates of gastric cancer patients (T3/T4 and/or N+) who have been initially treated with surgery. The major adverse reactions were Grade I and Grade II nausea and vomiting, as well as myelosuppression. CCRT is well tolerated.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy, Adjuvant; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Staging; Radiotherapy, Adjuvant; Radiotherapy, Intensity-Modulated; Stomach Neoplasms; Survival Rate; Tetrahydrofolates

The folate antagonist methotrexate (MTX) inhibits synthesis of tetrahydrofolate (THF), pyrimidines and purines, and induces differentiation in several cell types. At 1 microM, MTX reduced proliferation and induced differentiation in HT29 colon cancer cells; the latter effect was augmented (P < 0.001) by thymidine (100 microM) but was reversed (P < 0.001) by the purines, hypoxanthine (Hx; 100 microM) and adenosine (100 microM). In contrast 5-fluoro-uracil (5-FU), a specific thymidylate synthase (TS) inhibitor, had no effect on differentiation, suggesting that MTX-induced differentiation is not due to a reduction in thymidine but to the inhibition of purine biosynthesis. Inhibition of cyclic AMP (cAMP) by RpcAMP (25 microM) further enhanced (P < 0.001) MTX induced differentiation, whereas the cAMP activator forskolin (10 microM) reversed (P < 0.001) MTX induced differentiation. These observations implicate a central role of adenosine and cAMP in MTX induced differentiation. By combining Western blot analysis with liquid chromatography-mass spectrometry (LC-MS)and HPLC analyses we also reveal both the expression and activity of key enzymes (i.e. methionine synthase (MS), s-adenosylhomocysteinase, cystathionine beta-synthase and ornithine decarboxylase) regulating methyl cycle, transsulfuration and polyamine pathways in HT29 colon cancer cells. At 1 microM, MTX induced differentiation was associated with a marked reduction in the intracellular concentrations of adenosine and, consequently, S-adenosylmethionine (SAM), S-adenosylhomocysteine, polyamines and glutathione (GSH). Importantly, the marked reduction in methionine that accompanied MS inhibition following MTX treatment was non-limiting with respect to SAM synthesis. Collectively, these findings indicate that the effects of MTX on cellular differentiation and single carbon metabolism are primarily due to the intracellular depletion of purines.

Topics: Adenocarcinoma; Adenosine; Alkaline Phosphatase; Antimetabolites, Antineoplastic; Cell Differentiation; Cell Proliferation; Colonic Neoplasms; Cyclic AMP; Extracellular Signal-Regulated MAP Kinases; HT29 Cells; Humans; Hypoxanthines; MAP Kinase Kinase Kinases; Methionine; Methotrexate; Phosphatidylinositol 3-Kinases; Polyamines; Purines; Signal Transduction; Tetrahydrofolates; Thymidine

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drugs, Chinese Herbal; Female; Fluorouracil; Humans; Male; Middle Aged; Phytotherapy; Stomach Neoplasms; Tetrahydrofolates

Aberrant DNA methylation occurs in a subset of colorectal cancers and is characterized by regional areas of hypermethylation at CpG islands. The aims of this study were firstly to evaluate the levels of folate intermediates (FIs) in tumors with aberrant DNA methylation and secondly to determine whether these levels are affected by polymorphisms in key genes involved in folate metabolism.. The concentrations of two major intracellular FIs, 5,10-methylenetetrahydrofolate and tetrahydrofolate (FH4), were measured in 103 surgically resected colorectal cancers. DNA hypermethylation at seven different CpG islands was measured using the MethylLight assay. Genotyping for polymorphisms in the thymidylate synthase, cystathionine beta-synthase, methionine synthase, and methylenetetrahydrofolate reductase (MTHFR) genes was carried out using PCR and PCR-RFLP.. Significantly higher levels of FH4 were found in tumors from the proximal colon compared with those originating in the distal colon and rectum. Tumors with aberrant DNA methylation of CpG islands within promoter regions of the hMLH1, TIMP3, and ARF genes also contained higher levels of both 5,10-methylenetetrahydrofolate and FH4. In contrast, patients who were homozygous for the C667T polymorphism of the MTHFR gene had significantly lower concentrations of both these FIs in their tumor tissue.. The concentrations of FIs in colorectal tumors are directly related to the presence of frequent DNA hypermethylation and inversely related to the presence of a common polymorphism in the MTHFR gene. FIs could serve as biochemical markers for the risk of developing this disease, as well as for the prediction of toxicity and efficacy of fluorouracil-based treatments.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Adenocarcinoma; Adenoma; Aged; Colorectal Neoplasms; CpG Islands; Cystathionine beta-Synthase; DNA Methylation; Female; Genotype; Humans; Male; Methylenetetrahydrofolate Reductase (NADPH2); Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Tetrahydrofolates; Thymidylate Synthase

Currently, biochemical modulation for 5-fluorouracil (5-FU) is one of the most successful chemotherapy for both colo-rectal and gastric cancer. The purpose of this study is to evaluate the significance of measuring intratumoral thymidylate synthetase (TS) and folate (FH4) levels as predictive parameters for the successful treatment. Samples were collected from 16 advanced colo-rectal and 21 advanced gastric cancer. TS and tetrahydrofolate levels in the specimens were measured by binding assay. Results showed that there were no significant difference in TS levels between the different pathologic types of carcinoma. On the other hand, well (3.94 +/- 1.75 p mol/g) and moderately (5.95 +/- 2.69 p mol/g) differentiated carcinoma showed lower FH4 levels compared to poorly differentiated carcinoma (9.58 +/- 5.27 p mol/g). In conclusion, biochemical modulation by cisplatin or leucovorin, which elevates intratumoral folate levels, is more needed for well and moderately differentiated carcinoma. Finally, measuring TS levels can also be important because two cases who responded to cisplatin/5-FU chemotherapy showed low TS levels compared to the others who had lower response.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colonic Neoplasms; Fluorouracil; Humans; Stomach Neoplasms; Tetrahydrofolates; Thymidylate Synthase

Various factors, including thymidylate synthase, thymidine kinase, 5-fluorouracil phosphorylation and degradation pathways, folate concentrations, and the stability of ternary complex, which influence thymidylate synthase inhibition rate of fluoropyrimidines, were studied in 87 human adenocarcinoma tissues.. The activity of the 5-fluorouracil degradation pathway was not significantly lower than the activity of the 5-fluorouracil phosphorylation pathway. The activity of the catabolism pathway of 5-fluorouracil should be considered in human adenocarcinoma tissue during chemotherapy. On the other hand, the means plus or minus standard deviations (means +/- SD) of the concentration of 5,10-methylenetetrahydrofolate and tetrahydrofolate were 0.69 +/- 0.54 and 1.25 +/- 0.69 nM, respectively, for the adenocarcinoma tissues without previous chemotherapy.. Because the half-life of tritium-labeled ternary complex and folate concentration in cytosol were correlated well, the differences in folate concentration among tumors must influence the dynamic equilibrium of ternary complex formation. Moreover, these results show that the ratio of 5,10-methylenetetrahydrofolate concentration to thymidylate synthase concentration influences the thymidylate synthase inhibition rate in tumor, and that the new synthesis of 5,10-methylenetetrahydrofolate and tetrahydrofolate from other endogenous reduced folates is also important in tumors with high thymidylate synthase concentrations.

Topics: Adenocarcinoma; Colorectal Neoplasms; Culture Techniques; Fluorouracil; Folic Acid; Humans; Leucovorin; Lymph Nodes; Phosphorylation; Stomach Neoplasms; Tetrahydrofolates; Thymidine Kinase; Thymidylate Synthase