vitamin-b-12 and Adenocarcinoma

Several B vitamins are essential in the one-carbon metabolism pathway, which is central to DNA methylation, synthesis, and repair. Moreover, an imbalance in this pathway has been linked to certain types of cancers. Here, we performed a meta-analysis in order to investigate the relationship between the intake of four dietary one-carbon metabolism-related B vitamins (B2, B6, folate, and B12) and the risk of esophageal cancer (EC). We searched PubMed, Web of Science, and Embase for relevant studies published through 1 March 2018. The odds ratio (OR) with 95% confidence interval (CI) for the highest versus the lowest level of each dietary B vitamin was then calculated. From 21 articles reporting 26 studies including 6404 EC cases and 504,550 controls, we found an inverse correlation between the consumption of vitamin B6 and folate and the risk of EC; this association was specific to the US, Europe, and Australia, but was not found in Asia. A dose-response analysis revealed that each 100 μg/day increase in folate intake reduced the risk of EC by 12%. Moreover, each 1 mg/day increase in vitamin B6 intake decreased the risk of EC by 16%. Surprisingly, we found that each 1 μg/day increase in vitamin B12 intake increased the risk of esophageal adenocarcinoma by 2%, particularly in the US and Europe, suggesting both geographic and histological differences. Together, our results suggest that an increased intake of one-carbon metabolism-related B vitamins may protect against EC, with the exception of vitamin B12, which should be consumed in moderation.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Anticarcinogenic Agents; Diet; DNA Methylation; DNA Repair; DNA Replication; DNA, Neoplasm; Dose-Response Relationship, Drug; Esophageal Neoplasms; Female; Humans; Male; Middle Aged; Nutritional Status; Odds Ratio; Protective Factors; Recommended Dietary Allowances; Risk Assessment; Risk Factors; Risk Reduction Behavior; Vitamin B 12; Vitamin B Complex; Young Adult

The objectives of this single-center, open-label, phase II study were to evaluate (a) the feasibility and safety of neoadjuvant administration of pemetrexed with oral folic acid and vitamin B12 (FA/B12) in newly diagnosed patients with resectable rectal cancer and (b) intracellular and systemic vitamin metabolism. Patients were treated with three cycles of pemetrexed (500 mg/m, every 3 weeks) and FA/B12 before surgery. The reduced folates tetrahydrofolate, 5-methyltetrahydrofolate, and 5,10-methylenetetrahydrofolate were evaluated from biopsies in tumor tissue and in adjacent mucosa. Serum levels of homocysteine, cystathionine, and methylmalonic acid were also measured. All 37 patients received three cycles of pemetrexed; 89.2% completed their planned dosage within a 9-week feasibility time frame. Neither dose reductions nor study drug-related serious adverse events were reported. Reduced folate levels were significantly higher in tumor tissue compared with adjacent mucosa at baseline. After FA/B12 administration, tissue levels of reduced folates increased significantly and remained high during treatment in both tumor and mucosa until surgery. Serum levels of cystathionine increased significantly compared with baseline after FA/B12 administration, but then decreased, fluctuating cyclically during pemetrexed therapy. Homocysteine and methylmalonic acid levels decreased significantly after FA/B12 administration, and remained below baseline levels during the study. These results indicate that administration of three neoadjuvant cycles of single-agent pemetrexed, every 3 weeks, with FA/B12 in patients with resectable rectal cancer is feasible and tolerable. Tissue and serum vitamin metabolism results demonstrate the influence of pemetrexed and FA/B12 on vitamin metabolism and warrant further study.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cystathionine; Feasibility Studies; Female; Folic Acid; Folic Acid Antagonists; Homocysteine; Humans; Intestinal Mucosa; Male; Methylmalonic Acid; Middle Aged; Neoadjuvant Therapy; Pemetrexed; Rectal Neoplasms; Rectum; Vitamin B 12

To analyze the clinical efficacy and toxicity of vitamin support in lung adenocarcinoma patients treated with pemetrexed second-line chemotherapy.. Two hundred and eighty-three patients with stage 3/4 lung adenocarcinoma treated at our hospital from August 2010 to August 2013 were included in this study. The lung adenocarcinomas in all the 283 patients were confirmed by pathology or cytology, all were EGFR-negative, and all patients received pemetrexed second line chemotherapy. The 283 patients were randomly divided into two groups: the improved treatment group (142 cases) and the conventional treatment group (141 cases). The patients of conventional treatment group received 400 µg folic acid per os daily for 7 days before the first dose of pemetrexed, and continued until 21 days after the last dose of pemetrexed. Besides, they received 1000 µg vitamin B12 injection at 7 days before the first dose of pemetrexed, and once per cycle of pemetrexed for 3 cycles after the last dose of pemetrexed. The patients of the improved treatment group took 400 µg folic acid daily per os from the day before the first dose to 21 days after the last dose of pemetrexed. They also received 500 µg vitamin B12 by injection one day before the first dose, and one day before each therapy cycle of pemetrexed therapy.. The mean number of cycles of pemetrexed chemotherapy was 4 in both groups. In the 142 patients of improved treatment group, complete response (CR) was observed in two cases, partial remission (PR) in 28, stable disease (SD) in 21, and progressive disease (PD) in 91 cases, with a total effective rate of 21.1%. While in the conventional treatment group, CR was observed in one case, PR in 27 cases, SD in 23 cases, and PD in 90 cases, with a total effective rate of 19.9%. The median progression-free survival (PFS) was 3.8 months in the improved treatment group and 4.2 months in the conventional treatment group (P=0.143). The toxicity of chemotherapy was mild in both groups, with no significant difference between the two groups (P>0.05). The most common side effects of hematological system were leukopenia and neutropenia, and the most common side effects of non-blood system were nausea and vomiting. The most common grade 3-4 toxic reaction in both groups was leukopenia and neutropenia, with no significant difference between the two groups (P>0.05). Multivariate analysis showed that the age of patients was an independent factor of grade 3-4 chemotherapy toxic reaction (P<0.05), while gender, the baseline level of PS score or blood system had no significant effect on the grade 3-4 chemotherapy toxic reaction (P>0.05).. Compared with the conventional treatment scheme, the improved treatment scheme has similar therapeutic effects and could be used more conveniently, while the toxic effects of chemotherapy are not increased at the same time. Our results indicate that pemetrexed-based chemotherapy does not need to delay the chemotherapy because of vitamin support treatment.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Disease-Free Survival; Folic Acid; Humans; Lung Neoplasms; Pemetrexed; Treatment Outcome; Vitamin B 12; Vitamin B Complex

Pralatrexate is an antifolate designed for preferential tumor cell uptake and accumulation and received accelerated Food and Drug Administration approval in relapsed/refractory peripheral T-cell lymphoma. Pralatrexate 135 to 150 mg/m(2) every 2 weeks without vitamin supplementation was active in non-small cell lung cancer (NSCLC) although mucositis was dose limiting. This phase 1 study evaluated the safety of higher pralatrexate doses with vitamin supplementation to minimize toxicities.. Patients with stage IIIB/IV NSCLC received pralatrexate 150 to 325 mg/m(2) every 2 weeks with folic acid and vitamin B12 supplementation. Outcomes measured included adverse events (AEs), pharmacokinetics, and radiologic response.. Thirty-nine patients were treated for a median of two cycles (range 1-16+). Common treatment-related grade 3 and 4 AEs by dose (≤190 mg/m(2) and >190 mg/m(2)) included mucositis (33 and 40%) and fatigue (11 and 17%). Treatment-related serious AE (SAE) rates for doses ≤190 and >190 mg/m(2) were 0 and 20%, respectively. The response rate was 10% (95% confidence interval: 1-20%), including two patients with complete response (26+ and 32+ months) and two with partial response. Serum pralatrexate concentrations increased dose dependently up to 230 mg/m(2).. Pralatrexate with vitamin supplementation was safely administered to patients with previously treated NSCLC, and durable responses were observed. The recommended starting dose for phase 2 is 190 mg/m(2). A similar safety profile was observed in patients treated at 230 mg/m(2), although a higher serious AE rate was evident. Mucositis remains the dose-limiting toxicity of pralatrexate, and this study failed to demonstrate that vitamin supplementation prevents mucositis and failed to identify clinical predictors of mucositis. Individualized dose-modification strategies and prospective mucositis management will be necessary in future trials.

Topics: Adenocarcinoma; Aged; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Dietary Supplements; Female; Folic Acid; Folic Acid Antagonists; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Prognosis; Tissue Distribution; Vitamin B 12; Vitamin B Complex

Pemetrexed, an antifolate involved in purine and pyrimidine formation, is a potential alternative to fluoropyrimidines in the treatment of colorectal cancer. A phase I trial was performed to establish the maximum tolerated dose (MTD) of pemetrexed and oxaliplatin when B(12) and folate supplementation is used.. Patients with metastatic colorectal cancer received folate (> 350 microg) daily and vitamin B(12) (1000 microg) every 9 weeks starting 7 days before chemotherapy. Pemetrexed over 10 minutes and oxaliplatin over 2 hours were given every 3 weeks in escalating dose cohorts.. Twenty-two patients were entered on 6 dose levels. The MTD was established at the highest dose level, pemetrexed 900 mg/m(2) and oxaliplatin 130 mg/m(2). Toxicities related to treatment at the MTD included grade 3 neutropenia and thrombocytopenia. For all dose levels combined, grade 3/4 toxicities included hematologic, neurologic, and gastrointestinal. Nine of 21 evaluable patients responded overall (response rate, 43%). The time to tumor progression was 11.9 months.. The MTD was determined to be pemetrexed 900 mg/m(2) and oxaliplatin 130 mg/m(2) every 21 days when folate and B (12) supplementation are used. Because of the observed tolerability and activity of this regimen, further evaluation is warranted.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Folic Acid; Folic Acid Antagonists; Glutamates; Guanine; Humans; Male; Maximum Tolerated Dose; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pemetrexed; Survival Rate; Treatment Outcome; Vitamin B 12

Topics: Adenocarcinoma; alpha-Fetoproteins; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Vitamin B 12

X-Ray induced phototherapy is highly sought after as it provides a deep tissue, synergistic method of treating cancers via standard-of-care radiotherapy. When this is combined with releasable chemotherapy agents, it can provide high target selectivity, with reduced off-target organ effects that limit current systemic therapies. We have recently developed a unique light-activated drug delivery system whereby the drug is conjugated to an alkylcobalamin scaffold. Alkylcobalamins are actively transported into cells by transcobalamin receptors (TCblR), which are overexpressed in a variety of cancer types. We hope to utilize this cobalamin scaffold technology for drug delivery in pancreatic adenocarcinoma (PDAC) cancer.. The ability of the cobalamin scaffold to selectively target PDAC was investigated by treating mice that had MIA PaCa-2 xenografts with an alkylcobalamin labeled with the fluorophore Bodipy650 (Bodipy650-cobalamin). The mice were imaged alive and organs as well as tumors were subsequently imaged ex vivo. In addition, we examined the potential of the cobalamin scaffold to deliver drugs to orthotopic pancreas MIA PaCa-2 tumors with Bodipy650-cobalamin. We determined the light dose required for release of cargo from the cobalamin scaffold by examining the fluorescence increase of Bodipy650-cobalamin in response to red light (650 nm). Finally, we probed the ability of the cobalamin scaffold to release cargo with increasing X-ray doses from a clinical linear accelerator.. We have found that Bodipy650-cobalamin was shown to localize in MIA PaCa-2 tumors, both in flank and orthotopic models. We quantified a light dose for red light release from the cobalamin scaffold that is within normal clinical doses required for photodynamic therapy. This derivative was also activated with clinical X-ray doses from a linear accelerator.. Tumor selectivity combined with fluorescence detection demonstrates the effectiveness of the vitamin B

Topics: Adenocarcinoma; Animals; Mice; Pancreatic Neoplasms; Photochemotherapy; Photosensitizing Agents; Vitamin B 12; X-Rays

Pancreatic carcinoma is one of the most aggressive cancers overcoming chemoresistance. Thus, novel compounds to complement the current antitumor agents are in need. Ocoxin oral solution (OOS) has proven antioxidant, anti-inflammatory, and antistromagenic properties. The aim of this study was to analyze the effect of OOS in an experimental pancreatic cancer model and its implication in stroma-related chemoresistance to paclitaxel and gemcitabine.. Murine pancreatic carcinoma 266-6 cells were treated with OOS to analyze cell cycle and to perform a mRNA comparative microarray study. Then the viability was assessed in combination with paclitaxel and/or gemcitabine. Chemoresistance induced by the medium taken from fibroblast cultures was also investigated on 6 human pancreatic carcinoma cell lines. Furthermore, an experimental model of pancreatic cancer was carried out to study the effect of OOS in vivo.. Ocoxin oral solution enhances the cytotoxic effect of paclitaxel and gemcitabine, while it ameliorates the chemoresistance induced by fibroblast-derived soluble factors in human pancreatic cancer cells. The OOS also promotes the regulation of the expression of genes that are altered in pancreatic carcinoma and slows down 266-6 cell pancreatic tumor development in vivo.. Ocoxin oral solution could be a potential complement to the chemotherapeutic drugs for pancreatic adenocarcinoma.

Topics: Adenocarcinoma; Administration, Oral; Animals; Antineoplastic Agents; Ascorbic Acid; Cell Cycle; Cell Line; Cell Line, Tumor; Cell Survival; Deoxycytidine; Drug Resistance, Neoplasm; Folic Acid; Gemcitabine; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, Inbred C57BL; Neoplasms, Experimental; Paclitaxel; Pancreatic Neoplasms; Pantothenic Acid; Plant Extracts; Solutions; Vitamin B 12; Vitamin B 6; Zinc Sulfate

Gallbladder cancer (GBC) is relatively rare and usually has vague clinical presentation. Vitamin B12 (Cobalamin [Cbl]) deficiency is well recognized clinical entity, in contrast, elevated Cbl remains largely unknown and underestimated in practice. We report an elderly patient who presented with generalized weakness. She found to have elevated serum Cbl which raise the suspicion for malignancy. Subsequent imaging studies and tissue biopsy led to diagnose gallbladder adenocarcinoma. Elevated Cbl has been associated with increased risk of subsequent diagnosis of cancer. In addition, elevated Cbl levels in cancer patients have a strong predictive value for mortality, frequent metastases, and poor prognosis. In this case, the incidental finding of high Cbl level led to the diagnosis of serious illness which could otherwise present in a more advanced stage.

Topics: Adenocarcinoma; Aged; Female; Gallbladder Neoplasms; Humans; Vitamin B 12; Vitamin B 12 Deficiency

Gastric cancer is one of the leading causes of cancer mortality worldwide. Accumulating evidence suggests that vitamin B12 plays an important role in the development of gastric cancer. Genome-wide association studies on metabolites in the one-carbon metabolism pathway identified several vitamin B12-related polymorphisms. Therefore, we investigated the association between variants within vitamin B12-related genes and gastric cancer in a Han Chinese population. Eight variants within the genome were significant vitamin B12-related genes, and they were selected for analysis in this case-control study. This study used a total of 492 gastric cancer patients and 550 noncancer controls. The variant rs526934 from the TCN1 gene was associated with an increased risk of developing gastric cancer. Increased risks of gastric cancer occurrence were observed in the minor G allele (OR = 1.25, 95% CI = 1.03-1.52, P = 0.031) and GG genotype (OR = 2.06, 95% CI = 1.24-3.42, P = 0.0043) compared with the wild-type A allele and AA-GA genotype, respectively. In the haplotypic analysis, we found that the CUBN haplotypes were associated with an altered gastric cancer risk. The rs1801222T/rs11254363A (OR = 1.40, 95% CI = 1.05-1.86, P = 0.021) and rs1801222C/rs11254363G (OR = 4.39, 95% CI = 2.32-8.30, P < 0.0001) haplotypes exhibited an increased gastric cancer risk, while rs1801222T/rs11254363G showed protective effects against gastric cancer (OR = 0.43, 95% CI = 0.25-0.73, P = 0.002) compared with the wild-type rs1801222C/rs11254363A haplotype. The circulating vitamin B12 concentration-related variants were associated with the occurrence of gastric cancer. This finding shed light on the unexpected role of vitamin B12 metabolism genes in gastric carcinogenesis and highlighted the interplay of diet, genetics, and human cancers.

Topics: Adenocarcinoma; Aged; Alleles; Asian People; Case-Control Studies; Female; Fucosyltransferases; Galactoside 2-alpha-L-fucosyltransferase; Gene Expression Regulation, Neoplastic; Gene Frequency; Genome-Wide Association Study; Haplotypes; Humans; Male; Middle Aged; Neoplasm Staging; Polymorphism, Single Nucleotide; Receptors, Cell Surface; Risk Factors; Stomach Neoplasms; Transcobalamins; Vitamin B 12

B vitamins play an essential role in DNA synthesis and methylation, and may protect against oesophageal and gastric cancers. In this case-cohort study, subjects were enrolled from the General Population Nutrition Intervention Trial in Linxian, China. Subjects included 498 oesophageal squamous cell carcinomas (OSCCs), 255 gastric cardia adenocarcinomas (GCAs), and an age- and sex-matched sub-cohort of 947 individuals. Baseline serum riboflavin, pyridoxal phosphate (PLP), folate, vitamin B12, and flavin mononucleotide (FMN) were measured for all subjects. We estimated the associations with Cox proportional hazard models, with adjustment for potential confounders. Compared to those in the lowest quartile of serum riboflavin, those in the highest had a 44% lower risk of OSCC (HR: 0.56, 95% CI: 0.41 to 0.75). Serum vitamin B12 as a continuous variable was observed to be significantly inversely associated with OSCC (HR: 0.95, 95% CI: 0.89 to 1.01, P for score test = 0.041). Higher serum FMN levels were significantly associated with increased risk of OSCC (HR: 1.08, 95% CI: 1.01 to 1.16) and GCA (HR: 1.09, 95% CI: 1.00 to 1.20). Our study prompted that B vitamins have the potential role as chemopreventive agents for upper gastrointestinal cancers.

Topics: Adenocarcinoma; Adult; Aged; Carcinoma, Squamous Cell; Cardia; China; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Flavin Mononucleotide; Folic Acid; Humans; Male; Middle Aged; Niacin; Proportional Hazards Models; Prospective Studies; Pyridoxal Phosphate; Riboflavin; Stomach Neoplasms; Vitamin B 12; Vitamin B Complex

Pemetrexed is a novel, multitargeted antifolate approved for the treatment of malignant pleural mesothelioma and non-small cell lung cancer. Although pemetrexed is a safe drug, some adverse effects such as myelosupression and cutaneous reactions are observed. Pemetrexed-induced eyelid edema is a rare side effect of pemetrexed treatment, and until this moment few cases were reported in the medical literature. We reported a new case of pemetrexed-induced eyelid edema in a patient with adenocarcinoma of the lung with brain metastases.

Topics: Adenocarcinoma; Antineoplastic Agents; Brain Neoplasms; Carboplatin; Dexamethasone; Diuretics; Edema; Eyelid Diseases; Female; Folic Acid; Furosemide; Glucocorticoids; Glutamates; Guanine; Humans; Lung Neoplasms; Middle Aged; Pemetrexed; Vitamin B 12

The clinical phenotype of cobalamin (Cbl) deficiency is dictated by the essential role of this vitamin in two key enzymatic reactions. Multiple proteins and receptors participate in the absorption, transport and delivery of this vitamin to tissue cells. Cellular uptake of Cbl is mediated by transcobalamin (TC), a plasma protein and a transmembrane receptor (TCblR) with high affinity for TC saturated with Cbl. Knockdown of TCblR with siRNA results in decreased TC-Cbl uptake. The ensuing Cbl deficiency leads to an increase in doubling time and decreased proliferation of these cells. The study confirms the seminal role of this receptor in the cellular uptake of Cbl and its down-regulation as a potential strategy to inhibit proliferation of cancer cells.

Topics: Adenocarcinoma; Antigens, CD; Blotting, Western; Cell Proliferation; Colorectal Neoplasms; Humans; Kidney; Receptors, Cell Surface; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Vitamin B 12

Topics: Adenocarcinoma; Adult; Age Distribution; Age Factors; Aged; Aged, 80 and over; Aspirin; Barrett Esophagus; Clopidogrel; Drug Interactions; Drug Prescriptions; Esophageal Neoplasms; Esophagitis; Esophagoscopy; Gastroesophageal Reflux; Gastroscopy; Heartburn; Hip Fractures; Humans; Intestinal Absorption; Middle Aged; Obesity; Odds Ratio; Platelet Aggregation Inhibitors; Population Surveillance; Prevalence; Proton Pump Inhibitors; Ticlopidine; Vitamin B 12

Bronchioloalveolar carcinoma (BAC) and adenocarcinoma mixed subtype with bronchioloalveolar features (ADC-WBF) represent a unique anatomo-clinical entity accounting for some 20% of non-small cell lung cancers (NSCLC). These tumors seem less sensitive to chemotherapy than other NSCLC. We report two cases of advanced ADC-WBF treated with second-line and fourth-line pemetrexed. Major and durable radiological response associated with clinical and functional improvement was achieved in both patients, without important drug toxicity. After treatment arrest, the two patients experienced progressive disease but responded to retreatment with pemetrexed. Recent data suggest that paclitaxel-based chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors could be an acceptable therapeutic strategy in unresectable CBA and ADC-WBF. The cases reported here and preclinical findings suggest a therapeutic efficacy of pemetrexed in these tumors. Prospective studies are required to evaluate this hypothesis.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Aged; Antimetabolites, Antineoplastic; Bone Neoplasms; Cough; Disease Progression; Dyspnea; Folic Acid; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Neoplasm Staging; Neutropenia; Pemetrexed; Remission Induction; Renal Insufficiency; Smoking; Tomography, X-Ray Computed; Vitamin B 12

A 53-year-old woman was with adenocarcinoma of the lung metastatic to the brain was treated after several lines of chemotherapy with pemetrexed. After six cycles an impressive regression of the brain metastases was documented. A brief review of the literature on response of cerebral metastases to chemotherapy is added.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Brain Neoplasms; Chest Pain; Disease Progression; Dyspnea; Female; Folic Acid; Glutamates; Guanine; Headache; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Middle Aged; Neoplasm Staging; Pemetrexed; Radiotherapy; Remission Induction; Smoking; Thoracic Surgery; Vitamin B 12

Topics: Adenocarcinoma; Adolescent; Adult; Agammaglobulinemia; Anemia, Pernicious; Gastrectomy; Gastrointestinal Neoplasms; Genetic Diseases, X-Linked; Humans; Male; Recurrence; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adenocarcinoma; Gastrectomy; Humans; Injections, Intramuscular; Prognosis; Stomach Neoplasms; Time Factors; Vitamin B 12; Vitamin B 12 Deficiency

Methionine synthase (MTR) synthesizes methionine from homocysteine, using cobalamin as a cofactor and 5-methyltetrahydrofolate as a cosubstrate.. To determine the influence of homocystine (Hcy, dimer of homocysteine) in the presence of either cobalamin or methionine on the transcription and the activity of methionine synthase in Caco-2, a human adenocarcinoma cell line.. Methionine synthase activity and quantification of its mRNA by real-time RT-PCR were determined in cells cultivated under four differents conditions: Hcy with cobalamin (Hcy+ Cbl+), Hcy with methionine (Hcy+Met+), methionine with Cbl (Met+ Cbl+) and methionine only (Met+).. Activity (nmol/h/mg protein) was maximal in cells cultivated in Hcy+Cbl+ (2.45 +/- 0.35), compared to cells cultivated in Hcy+Met+ (0.18 +/- 0.01, p<0.001), in Met+ Cbl+ (1.60 +/- 0.06, p<0.05), and in Met+ (0.40 +/- 0.05, p<0.001), suggesting an adaptation of the cells to requirement in synthesized methionine. The mRNA level of MTR in Hcy+ Cbl+ and Hcy+Met+ (2.82 +/-0.49 and 3.33 +/- 0.48 AU, respectively ) was about 2.5 / 3.0-fold higher than that in Met+ Cbl+ and in Met+ (1.00 +/-0.13 and 1.20 +/-0.20 AU, respectively, p<0.001).. Methionine synthase expression of Caco-2 cell is under a transcriptional control influenced by Hcy.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Adenocarcinoma; Caco-2 Cells; Gene Expression Regulation, Neoplastic; Homocysteine; Humans; Methionine; RNA, Messenger; Transcription, Genetic; Up-Regulation; Vitamin B 12

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Bezoars; Cecum; Colonic Neoplasms; Emergencies; Female; Humans; Intestinal Obstruction; Radiography; Tablets; Vitamin B 12

Human colon adenocarcinoma (Caco-2) cells express both intrinsic factor-cobalamin receptor and transcobalamin II (TC II). The expression of these activities began to rise by day 6 and reached peak levels between 10 and 15 days in culture. The postconfluent Caco-2 cell membranes bound approximately 30-35 fmol of intrinsic factor (IF) [57Co]Cbl/mg protein. The size of the mature receptor expressed in the apical brush border had a relative molecular mass of 230 kDa. The intracellular form of TC II had a Mr of 43, 5 higher than the secreted form of TC II. TC II was secreted unidirectionally via the basolateral direction when Caco-2 cells were grown on culture inserts. When grown on culture inserts, the Caco-2 cells were polarized (electrical resistance greater than 200 omega/cm2) and transcytosed [57Co]Cbl bound to IF from apical-to-basal but not from basal-to-apical direction. Under these conditions, [57Co]Cbl complexed to haptocorrin was not transported. These cells also transcytosed free [57Co]Cbl, although less efficiently. The [57Co]Cbl transcytosed using either IF[57Co]Cbl or free [57Co]Cbl as ligands was bound exclusively to TC II. Intracellular [57Co]Cbl decreased during transcytosis with a slow (t1/2 = 4 h) transfer of [57Co]Cbl from IF to TC II. These results show that the transport of Cbl in Caco-2 cells is very similar to the human enterocyte system.

Topics: Adenocarcinoma; Biological Transport; Cell Line; Colonic Neoplasms; Electrophoresis, Polyacrylamide Gel; Humans; Intrinsic Factor; Kinetics; Methionine; Molecular Weight; Sulfur Radioisotopes; Transcobalamins; Vitamin B 12

Because of the importance of homocysteine thiolactone metabolism in the growth of normal tissues, and because of abnormal metabolism of homocysteine thiolactone in malignant cells, N-substituted derivatives of homocysteine thiolactone were synthesized and assayed for antineoplastic and anticarcinogenic activities. A single dose of 2.5 mg/kg of the synthetic derivative, N-homocysteine thiolactonyl retinamido cobalamin, injected directly into subcutaneous human pancreatic adenocarcinoma neoplasms in athymic mice, caused 50% inhibition of growth without evidence of toxicity. The findings suggest a novel approach to counteracting the growth of malignant neoplasms and support the hypothesis of a deficiency of an N-homocysteine thiolactonyl derivative in malignant cells.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cell Division; Homocysteine; Humans; Male; Mice; Mice, Nude; Neoplasms, Experimental; Pancreatic Neoplasms; Tumor Cells, Cultured; Vitamin B 12

The distribution of cobalamin coenzyme precursor, 57Co-cyanocobalamin (57Co-CN-Cbl), in normal animals and in mammary adenocarcinoma (AC 755) and La leukemia-bearing mice has been studied during the exponential phase of tumour growth. The total uptake of radioactivity in the normal target organs was different. AC 755 took up 57Co-CN-Cbl selectively in all the periods of observation. In the case of La leukemia the highest rate of 57Co-CN-Cbl uptake in the spleen was found before its maximal hyperplasia. The accumulation of radioactivity in tumours led to a significant decrease in the total labelled cobalamin levels of the liver and kidneys. Analysis of the obtained kinetic curves revealed a different ability of AC 755 and leukemia cells for utilizing the pool of the endogenous cobalamin.

Topics: Adenocarcinoma; Animals; Cobalt Radioisotopes; Female; Kidney; Kinetics; Leukemia, Experimental; Liver; Mammary Neoplasms, Experimental; Mice; Neoplasm Transplantation; Spleen; Time Factors; Tissue Distribution; Vitamin B 12

Topics: Adenocarcinoma; Animals; Cobamides; Drug Evaluation, Preclinical; Hematopoietic Stem Cells; Male; Mammary Neoplasms, Experimental; Methotrexate; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Splenic Neoplasms; Vitamin B 12

The effect of methylcobalamin on 3H-methotrexate uptake by tumor and normal tissues of mice with mammary adenocarcinoma (Ca-755) was studied. Methylcobalamin stimulated the rate of 3H-methotrexate influx into the tumor and small intestine but did not change its influx into the spleen. The effect was dependent on the dose of methylcobalamin. Comparative analysis of the kinetic differences in 3H-methotrexate influx and efflux in tumor and susceptible host tissues revealed the optimal dose of methylcobalamin 0.01 mg/kg to improve the antitumor drug action.

Topics: Adenocarcinoma; Animals; Biological Transport; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Synergism; Female; Intestine, Small; Kinetics; Mammary Neoplasms, Experimental; Methotrexate; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Spleen; Vitamin B 12

This study was designed to examine the endogenous concentrations of 5,10-methylenetetrahydrofolate (CH2FH4) in human colorectal adenocarcinoma xenografts, and to determine the ability of other folate derivatives to increase the formation of the ternary covalent complex between CH2FH4, [6-3H]-5-fluorodeoxyuridylate (FdUMP) and thymidylate synthetase (TS, EC 2.1.1.45). Levels of CH2FH4 were determined by measuring the release of [3H]2O from [5-3H]-dUMP using TS from Lactobacillus casei. The reaction was linear from 1.9 X 10(-13) to 2.4 X 10(-11) mol of CH2FH4 assayed. Concentrations of CH2FH4 were low, ranging from 66 to 233 nM in cell water. Tetrahydrofolate (FH4) and dihydrofolate (FH2) increased complex formation, while 5-formyltetrahydrofolate (5-CHOFH4) and 5-methyltetrahydrofolate (5-CH3FH4) decreased the covalent binding of [6-3H]-FdUMP in vitro. Administration of FH4 or FH2 to tumor-bearing mice reduced subsequent formation of the covalent complex in vitro. Since 5-CH3FH4 is a major derivative of folate in mammalian tissues, its effect on the covalent binding of [6-3H]-FdUMP was examined further; even in the presence of homocysteine and cyanocobalamin (B12), the formation of the covalent complex was not increased. The fate of [5-14CH3]-FH4 was subsequently examined in vivo. In tumors at 1 hr after injection, 72% of the radiolabel remained as [5-14CH3]-FH4, while 17% had been converted to [14C]-methionine or incorporated into protein. By contrast, however, the incorporation of radiolabel into the protein fraction of liver was almost 30-fold greater at this time. At 4 hr, radioactivity in tumors (dpm/g) and in the fraction associated with [5-14CH3]-FH4 was decreased by over 60%, while metabolism was increased by only 13%. No polyglutamate forms of [5-14CH3]-FH4 were detected in tumors at 4 hr after treatment.

Topics: Adenocarcinoma; Animals; Cell Line; Colonic Neoplasms; Deoxyuracil Nucleotides; Female; Fluorodeoxyuridylate; Folic Acid; Homocysteine; Humans; Methyltransferases; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Rectal Neoplasms; Tetrahydrofolates; Thymidylate Synthase; Transplantation, Heterologous; Vitamin B 12

Methylcobalamin (10 microgram/kg bw, intramuscularly, on the 3d and 5th days after tumor transplantation) or methylcobalamin chlorpalladat -- MeCbl.PdCl3 (250 mg/kg bw in 2% starch suspension per os on the 2d and 6th days) were given to C57BI mice bearing adenocarcinoma Ca--755. On the 8th day after transplantation the methionine synthetase activity and proliferative pool of tumor cells were estimated. It has been disclosed that under the effect of MeCbl the activity of methionine synthetase rises concurrently with an increase in pool of the proliferating cells. Inhibition of tumor growth (by 80--90%) after the treatment with MeCbl.PdCl3 correlated with a decrease in the holoenzyme level in tumor cells.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Adenocarcinoma; Animals; Female; Mammary Neoplasms, Experimental; Methyltransferases; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Organometallic Compounds; Palladium; Vitamin B 12

The mechanism of the stimulant effect of methylcobalamine on the growth of mouse adenocarcinoma 755 was studied. More rapid growth of adenocarcinoma 755 under the cobalamine coentzyme effect is consequent on an increased proliferative pool with the stable parameters of the mitotic cycle and minimal death of tumour cells. Apparently, inhibition of DNA synthesis in the greater S-phase cell subpopulation potentiated the antitumour effect of methotrexate combined with methylcobalamine.

Topics: Adenocarcinoma; Animals; Cell Transformation, Neoplastic; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Female; Kinetics; Mammary Neoplasms, Experimental; Methotrexate; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Stimulation, Chemical; Vitamin B 12

Topics: Adenocarcinoma; Animals; Drug Therapy, Combination; Female; Folic Acid Antagonists; Hybridization, Genetic; Intestinal Neoplasms; Leukemia, Experimental; Mammary Neoplasms, Experimental; Methotrexate; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Inbred Strains; Neoplasms, Experimental; Quinolinium Compounds; Uterine Cervical Neoplasms; Vitamin B 12

The increasing number of publications about the incidence of cancer in small intestine with Crohn's disease shows Ileitis terminalis as an affection promoting cancer. Main problems are early diagnosis and differential diagnosis concerning intestinal stenosis caused by Crohn's recidivation or blind loop after resection. Regular scrutiny of patients with Crohn's disease is of special significance; because of the few present case reports early resection as prophylaxis is not justified.

Topics: Adenocarcinoma; Adult; Crohn Disease; Female; Humans; Ileal Neoplasms; Ileostomy; Intestinal Fistula; Malabsorption Syndromes; Middle Aged; Neoplasm Metastasis; Vitamin B 12

Elevation of transcobalamin I and serum vitamin B12 levels has usually been associated with increased granulocytic proliferation, such as occurs in chronic myelogenous leukemia. Two patients with metastatic cancer had extremely high serum vitamin B12 and transcobalamin I levels--greater than those seen in even the most intense granulocytic proliferation--that were not explainable by leukocytosis. The subjects' serum vitamin B12 levels were 18,750 and 21,221 pg per milliliter (normal, 471 plus or minus 174 pg per milliliter, mean plus or minus S.D.) and unsaturated vitamin B12 binding capacity 158,750 and 5,400 pg per milliliter (normal, 1153 plus or minus 313 pg per milliliter) respectively. The abnormally elevated serum binder was shown to be identical with transcobalamin balamin I in every respect. Levels of transcobalamin II and serum third binder were normal. The cause of the binder abnormality is unknown, but factors other than granulocyte proliferation may control or contribute to the production or accumulation of transcobalamin I.

Topics: Adenocarcinoma; Aged; Animals; Blood Proteins; Carcinoma; Carrier Proteins; Cell Division; Chromatography, DEAE-Cellulose; Chromatography, Gel; Cobalt Radioisotopes; Colonic Neoplasms; Female; Granulocytes; Humans; Immune Sera; Leukemia, Myeloid; Leukocyte Count; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Protein Binding; Rabbits; Radioligand Assay; Saliva; Stomach Neoplasms; Vitamin B 12

A series of 130 consecutive outpatients with recurrent aphthous stomatitis were screened at the oral medicine department, Glasgow Dental Hospital, for deficienciesin vitamin b12, folic acid, and iron. In 23 patients (17.7%) such deficiencies werefound; five were deficient in vitamin B12, seven in folic acid, and 15 in iron. Four had more than one deficiency. Out of 130 controls matched for age and sex 11 (8.5%) were found to have deficiencies. The 23 deficient patients with recurrent aphthaewere treated with specific replacement therapy, and all 130 patients were followed up for at least one year. Of the 23 patients on replacement therapy 15 showed complete remission of ulceration and eight definite improvement. Of the 107 patientswith no deficiency receiving local symptomatic treatment only 33 had a remission or wereimproved. This difference was significant (P less than 0.001). Most patients withproved vitamin B12 or folic acid deficiency improved rapidly on replacement therapy;those with iron deficiency showed a less dramatic response. The 23 deficient patientswere further investigated to determine the cause of their deficiencies and detect the presence of any associated conditions. Four were found to have Addisonian perniciousanaemia. Seven had a malabsorption syndrome, which in five proved to be a gluten-induced enteropathy. In addition, there were single patients with idiopathic proctocolitis, diverticular disease of the colon, regional enterocolitis, and adenocarcinoma of thecaecum. We suggest that the high incidence of deficiencies found in this series andthe good response to replacement therapy shows the need for haematological screening of such patients.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Anemia, Pernicious; Cecal Neoplasms; Child; Colitis; Crohn Disease; Diverticulum, Colon; Female; Folic Acid; Folic Acid Deficiency; Humans; Iron; Iron Deficiencies; Malabsorption Syndromes; Male; Middle Aged; Proctitis; Recurrence; Stomatitis, Aphthous; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adenocarcinoma; Female; Follow-Up Studies; Gastrectomy; Humans; Male; Middle Aged; Prognosis; Stomach Neoplasms; Vitamin B 12

Topics: Adenocarcinoma; Anemia; Anemia, Pernicious; Biological Assay; Blood; Cobalt Isotopes; Gastrectomy; Gastric Acidity Determination; Geriatrics; Histamine; Humans; Intrinsic Factor; Lactobacillus; Liver; Lymphoma; Schilling Test; Stomach Neoplasms; Urine; Vitamin B 12