vitamin-b-12 and Cell-Transformation--Neoplastic

Cell replication is tightly controlled in normal tissues and aberrant during disease progression, such as in tumorigenesis. The replication of cells can be divided into four distinct phases: Gap 1 (G1), synthesis (S), gap 2 (G2), and mitosis (M). The progression from one phase to the next is intricately regulated and has many "checkpoints" that take into account cellular status and environmental cues. Among the modulators of cell cycle progression are specific nutrients, which function as energy sources or regulate the production and/or function of proteins needed to advance cells through a replicative cycle. In this review, we focus on the roles of specific nutrients (vitamin A, vitamin D, iron, folic acid, vitamin B12, zinc, and glucose) in the control of cell cycle progression and discuss how insights into the mechanisms by which these nutrients modulate this process can be and have been used to control aberrant cell growth in the treatment of prevalent pathologies.

Topics: Cell Cycle; Cell Division; Cell Transformation, Neoplastic; Diet; Disease Progression; Folic Acid; Glucose; Humans; Iron; Signal Transduction; Vitamin A; Vitamin B 12; Vitamin D; Zinc

Topics: Aneuploidy; Basophils; Blood Platelets; Cell Transformation, Neoplastic; Child; Clinical Enzyme Tests; Cytogenetics; Eosinophilia; Fetal Hemoglobin; Fever; Hematologic Diseases; Humans; Leukemia, Myeloid; Leukocyte Count; Lymphatic Diseases; Muramidase; Primary Myelofibrosis; Prognosis; Skin Manifestations; Thrombocytosis; Vitamin B 12

Disorders in the metabolism of homocysteine and B vitamins, which are involved in a one-carbon transfer reaction and important for DNA synthesis and methylation, have been hypothesized to be associated with carcinogenesis. The purpose of this study is to evalu-ate the levels of homocysteine, vitamin B12 and folic acid in patients with newly diagnosed lung cancer and determines whether they might be used as an accurate tumor marker for monitoring the patients if they are found to be elevated in lung cancer.. Forty male patients with lung cancer were included in this study. Age-matched forty healthy males who had not malignant disease or had not received any drug affecting plasma homocysteine levels were selected as control group. Homocysteine, vitamin B12 and folate levels were measured in the samples obtained from the patients and controls.. Mean age of the patients with lung cancer was 58.7 ± 9.9 years. All the patients were cigarettes smokers. Mean daily consumption of cigarettes was 2.0±0.7 packs and mean duration of smoking was 30 ± 11 years. Histologic type of carcinoma was found to be squamous cell carcinoma in 55%, adenocarcinoma - in 35%, and small cell carcinoma - in 10% of the cases. Clinical stage was stage IA in 20%, stage IB - in 20%, stage IIA - in 2.5%, stage IIB - in 10%, stage IIIA - in 12.5%, stage IIIB - in 20%, and stage IV - in 15% of the cases. Mean homocysteine level was 15.3 ± 7.3 µmol/l in the patients with lung cancer while 9.8 ± 2.6 µmol/l in controls. Homocysteine level was significantly higher in the patients with lung cancer compared to control group (p < 0.001). Mean folate level was 4.3 ± 1.8 pg/ml in cancer cases while 6.1 ± 2.3 pg/ml in controls. That is to say, plasma folate levels were significantly lower in cases of lung cancer compared to controls (p < 0.001). There was no significantly difference between groups with regard to B12 levels (mean B12 level was 234 ± 99 and 240 ± 104 ng/ml in the patients with lung cancer and controls, respectively, p = 0.78). Plasma homocysteine, vitamin B12 and folate levels did not show significant difference with respect to histologic type of carcinoma. No significant correlation was found between plasma homocysteine, vitamin B12, folate levels and number of cigarettes smoked per day, duration of smoking, age of the patient, and clinical stage of carcinoma. There was also no correlation between number of cigarettes smoked per day, duration of smoking, age of the patient and clinical stage of carcinoma. A possible inverse correlation between plasma homocysteine, vitamin B12 and folate levels was not observed.. In conclusion, high plasma homocysteine and low folate levels could be associated with lung cancer. However, further studies performed on large patient population are needed.

Topics: Adult; Aged; Case-Control Studies; Cell Transformation, Neoplastic; Folic Acid; Homocysteine; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Retrospective Studies; Vitamin B 12

Persistent oncogenic human papillomavirus (HPV) infection is associated with cervical dysplasia. Cofactors, such as nutrient status, may be required for the progression of HPV infection to neoplasia. HPV DNA methylation patterns in vitro have been shown to be associated with viral transcriptional activity. Folate, vitamin B12, vitamin B6, and methionine may function to prevent cervical cancer through their role in DNA methylation. This study was conducted to examine the relationship of dietary intake of folate, vitamin B12, vitamin B6, and methionine, as well as circulating levels of folate and vitamin B12 to HPV persistence. Oncogenic HPV status was determined at baseline and at approximately 3 and 9 months postbaseline. Multivariate logistic regression analysis was used to determine the adjusted odds ratios for persistent HPV infection associated with each tertile of individual nutrient among 201 women with a persistent or intermittent HPV infection. Circulating vitamin B12 levels were inversely associated with HPV persistence (P for trend, 0.037) after adjusting for age, age at first intercourse, marital status, cigarette smoking status, race, and body mass index. In addition, women with circulating levels in the highest tertile (>493.2 pg/ml) of vitamin B12 were less likely to have a persistent infection (adjusted odds ratio = 0.4; 95% confidence interval = 0.17-0.96). No significant associations were observed between HPV persistence and dietary intake of folate, vitamin B12, vitamin B6, or methionine from food alone or from food and supplements combined or from circulating folate. These data suggest a role for circulating vitamin B12 in early cervical carcinogenesis.

Topics: Adolescent; Adult; Cell Transformation, Neoplastic; Cohort Studies; DNA Methylation; DNA, Viral; Female; Humans; Nutritional Status; Odds Ratio; Papillomaviridae; Papillomavirus Infections; Regression Analysis; Tumor Virus Infections; Uterine Cervical Neoplasms; Vitamin B 12

The cytotoxic effect of cobalamin (vitamin B12) on the growth of malignant and nonmalignant cell lines in culture has been examined. Among the four cobalamins studied, 5'-deoxyadenosylcobalamin, an enzymatically active derivative, was an effective cytotoxic agent. The data indicated that adenosylcobalamin seemed to act selectively on fast-growing malignant cells. Methylcobalamin was also effective at elevated concentrations. Cyanocobalamin was not toxic to all cell lines studied. Hydroxocobalamin at very high concentrations was able to slightly decrease growth of certain cell lines. The results support the hypothesis that the cytotoxic effect of cobalamin was associated with the metabolic activities of this vitamin at the cellular level. Also, cobalamin may be a potential antitumor agent.

Topics: Animals; Blood Cells; Cell Transformation, Neoplastic; Cells, Cultured; Connective Tissue; Connective Tissue Cells; Fibrosarcoma; Humans; Leukemia L1210; Lung; Lymphoma; Male; Mice; Tumor Cells, Cultured; Vitamin B 12

Plasma membrane receptors for the serum cobalamin-binding protein transcobalamin II (TCII) were identified on human leukemia K562 and HL-60 cells using immunoaffinity-purified human TCII labeled with [57Co]cyanocobalamin. The Bmax values for TCII receptors on proliferating K562 and HL-60 cells were 4,500 and 2,700 per cell, respectively. Corresponding dissociation constants (kd) were 8.0 x 10(-11) mol/L and 9.0 x 10(-11) mol/L. Rabbit TCII also bound to K562 and HL-60 cells but with slightly reduced affinities. Calcium was required for the binding of transcobalamin II to K562 cells. Brief treatment of these cells with trypsin resulted in almost total loss of surface binding activity. After removal of trypsin, surface receptors for TCII slowly reappeared, reaching pretrypsin treatment densities only after 24 hours. Reappearance of receptors was blocked by cycloheximide. TCII receptor densities on K562 and HL-60 cells correlated inversely with the concentration of cobalamin in the culture medium. This suggests that intracellular stores of cobalamin may affect the expression of transcobalamin receptors. Nonproliferating stationary-phase K562 cells had low TCII receptor densities (less than 1,200 receptors/cell). However, the density of TCII receptors increased substantially when cells were subcultured in fresh medium. Up-regulation of receptor expression coincided with increased 3H-thymidine incorporation, which preceded the resumption of cellular proliferation as measured by cell density. In the presence of cytosine arabinoside, which induces erythroid differentiation, K562 cells down-regulated expression of TCII receptors. When HL-60 cells were subcultured in fresh medium containing dimethysulfoxide to induce granulocytic differentiation, the up-regulation of TCII receptors was suppressed. This event occurred well before a diminution of 3H-thymidine incorporation and cessation of proliferation. Thus, changes in the regulation of expression of TCII receptors correlate with both the proliferative and differentiation status of cells.

Topics: Cell Division; Cell Line; Cell Membrane; Cell Transformation, Neoplastic; Cobalt Radioisotopes; Cytarabine; Dose-Response Relationship, Drug; Down-Regulation; Gene Expression; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Experimental; Leukemia, Myeloid; Receptors, Cell Surface; Transcobalamins; Trypsin; Up-Regulation; Vitamin B 12

Binding and uptake of transcobalamin II-bound cobalamin by HL-60 promyelocytic leukemia cells proceed through receptor-mediated endocytosis. The affinity constant of the receptor for transcobalamin II-cobalamin was found to be 6.1 liter/nmol and the maximal rate of uptake 12 pmol/10(9) cells/h. This uptake is mediated by about 3000 receptor sites per cell. Evidence is presented that the receptor recirculates from the cell surface to the lysosomes and vice versa. Upon differentiation induction of the cells by either DMSO in granulocytic direction or by 1,25-dihydroxy-vitamin D3 in monocytic direction a rapid decline in cellular uptake and cell surface binding of the protein-bound vitamin ensues. In particular the internalization of the complex decreases faster than all other observed signs of the ongoing differentiation process, such as reduction in the OKT9-reactive transferrin receptor, increase in lineage-specific surface markers, and decrease in [3H]thymidine incorporation and actual cell proliferation. The transcobalamin II receptor on the cell surface appears to be a proliferation-associated membrane component in human leukemic cells.

Topics: Calcitriol; Cell Line; Cell Transformation, Neoplastic; Cycloheximide; Dimethyl Sulfoxide; Endocytosis; Humans; Leukemia, Promyelocytic, Acute; Monensin; Receptors, Cell Surface; Transcobalamins; Tumor Cells, Cultured; Vitamin B 12

The enzyme N5-methyltetrahydrofolate:homocysteine methyltransferase (methionine synthetase) catalyzes the synthesis of methionine from homocysteine. Methylcobalamin is a cofactor for the reaction. The effects of methionine deprivation and methylcobalamin supplementation on the growth of normal and transformed rat liver epithelial cell lines were determined using growth constants to quantitate cell proliferation. No marked specific requirement by the transformed cell lines for methionine relative to leucine was observed. A sigmoidal relationship, however, was found to exist between growth constants and the logarithms of the amino acid concentrations for both normal and transformed cells. Methylcobalamin stimulated the growth rates of the normal and transformed liver cells in methionine-deficient, homocysteine-containing medium. Growth on methionine was not increased by the addition of methylcobalamin. The growth constants for two normal, two spontaneously transformed, one chemically transformed, and one tumor cell line grown in medium in which methionine was replaced by homocysteine were found to be proportional to the level of methionine synthetase. The results demonstrate the utility of growth quantitation to study the methionine dependency of transformed cells.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Animals; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Culture Media; Homocysteine; Leucine; Liver; Methionine; Rats; 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: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Animals; Cell Line; Cell Survival; Cell Transformation, Neoplastic; Cricetinae; Folic Acid; Homocysteine; Kidney; Methionine; Methylenetetrahydrofolate Dehydrogenase (NADP); Simian virus 40; Tetrahydrofolates; Vitamin B 12

Topics: Aged; Anemia, Pernicious; Cell Transformation, Neoplastic; Humans; Leukemia, Lymphoid; Lymphocytes; Middle Aged; Vitamin B 12