vitamin-b-12 and Lung-Neoplasms

Pemetrexed (ALIMTA, LY231514, MTA) is a novel antimetabolite that inhibits at least three enzymes involved in the folate pathway. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated clinical activity in non-small cell lung cancer as well as in a broad array of other solid tumors, including mesothelioma, breast, colorectal, bladder, cervical, gastric and pancreatic cancer. In non-small cell lung cancer, single-agent activity has been documented in the first- and second-line settings in Phase II and Phase III trials. Promising activity has also been demonstrated when pemetrexed is combined with platinum compounds (cisplatin, carboplatin, and oxaliplatin), vinorelbine, and gemcitabine. Low level dietary supplement of folic acid and vitamin B12 has significantly decreased the mucosal and bone marrow toxicity of pemetrexed without compromising its antitumor effect.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Folic Acid; Glutamates; Guanine; Humans; Lung Neoplasms; Neoplasms; Pemetrexed; Platinum Compounds; Thymidylate Synthase; Vitamin B 12

The novel multitargeted antimetabolite pemetrexed (Alimta), recently approved by the US Food and Drug Administration for the treatment of mesothelioma when combined with cisplatin, is also active in first- and second-line non-small-cell lung cancer (NSCLC). In a phase III trial comparing single-agent pemetrexed vs docetaxel (Taxotere) as second-line therapy in advanced NSCLC, survival was shown to be comparable between these agents, but side effects were significantly less frequent and severe for patients who received pemetrexed. In the frontline setting, phase II studies have shown significant activity and a very favorable toxicity profile of the combination of pemetrexed with a platinum agent. Pemetrexed has been well tolerated at systemic doses as a radiosensitizer when given as concurrent chest radiation, and a phase I study is under way to assess its tolerability in combination with carboplatin (Paraplatin) in this setting. Pemetrexed is an important addition to the armamentarium of medicines used to treat thoracic malignancies, and merits study in combination with other drugs having novel mechanisms of action.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Dietary Supplements; Folic Acid; Glutamates; Guanine; Hematinics; Humans; Lung Neoplasms; Mesothelioma; Pemetrexed; Thymidylate Synthase; Vitamin B 12

Since a high concentration of beta-carotene in blood reduces the risk of lung cancer, a large-scale intervention examination containing beta-carotene was conducted, mainly by the National Cancer Institute. The results showed that the risk of lung cancer increased with administration of beta-carotene. This result demonstrates that continuation of smoking is an important factor in the increased risk, and not smoking is confirmed to be the most important prevention method. The authors examined the treatment effect of raising the concentration of folic acid and vitamin B12 in blood on bronchial dysplasia as a pre-cancerous lesion. A significant medical treatment effect was see in the folic acid and vitamin B12 medication groups, which seems promising for the chemoprevention of lung cancer.

Topics: beta Carotene; Bronchi; Drug Administration Schedule; Drug Therapy, Combination; Folic Acid; Humans; Lung Neoplasms; Metaplasia; Smoking Cessation; Vitamin B 12

Pemetrexed (Alimta , LY231514) is a new multitargeted antifolate that inhibits several enzymes involved in the folate pathway. Pemetrexed is a potent inhibitor of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated clinical activity in non-small-cell lung cancer (NSCLC) as well as in a broad array of other solid tumors including mesothelioma and breast, colorectal, bladder, cervical, gastric, and pancreatic cancer. In NSCLC, single-agent activity has been documented in the first- and second-line settings. Promising activity has also been demonstrated when pemetrexed is combined with cisplatin, vinorelbine, oxaliplatin, carboplatin, and gemcitabine. Low-level dietary supplement of folic acid and vitamin B12 has significantly improved the safety profile of pemetrexed without compromising its antitumor effect. In this review, the pharmacology and clinical activity of pemetrexed in NSCLC cancer is discussed.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Glutamates; Guanine; Humans; Lung Neoplasms; Pemetrexed; Vitamin B 12

Although vitamin deficiency is encountered infrequently in developed countries, inadequate intake of several vitamins is associated with chronic disease.. To review the clinically important vitamins with regard to their biological effects, food sources, deficiency syndromes, potential for toxicity, and relationship to chronic disease.. We searched MEDLINE for English-language articles about vitamins in relation to chronic diseases and their references published from 1966 through January 11, 2002.. We reviewed articles jointly for the most clinically important information, emphasizing randomized trials where available.. Our review of 9 vitamins showed that elderly people, vegans, alcohol-dependent individuals, and patients with malabsorption are at higher risk of inadequate intake or absorption of several vitamins. Excessive doses of vitamin A during early pregnancy and fat-soluble vitamins taken anytime may result in adverse outcomes. Inadequate folate status is associated with neural tube defect and some cancers. Folate and vitamins B(6) and B(12) are required for homocysteine metabolism and are associated with coronary heart disease risk. Vitamin E and lycopene may decrease the risk of prostate cancer. Vitamin D is associated with decreased occurrence of fractures when taken with calcium.. Some groups of patients are at higher risk for vitamin deficiency and suboptimal vitamin status. Many physicians may be unaware of common food sources of vitamins or unsure which vitamins they should recommend for their patients. Vitamin excess is possible with supplementation, particularly for fat-soluble vitamins. Inadequate intake of several vitamins has been linked to chronic diseases, including coronary heart disease, cancer, and osteoporosis

Topics: Ascorbic Acid; Avitaminosis; Blood Coagulation; Breast Neoplasms; Carotenoids; Chronic Disease; Colorectal Neoplasms; Coronary Disease; Dietary Supplements; Female; Folic Acid; Fractures, Bone; Humans; Lung Neoplasms; Male; Neoplasms; Neural Tube Defects; Prostatic Neoplasms; Risk Factors; Vitamin A; Vitamin B 12; Vitamin B 6; Vitamin D; Vitamin E; Vitamin K; Vitamins

Lung cancer is the leading cause of cancer death in the United States and throughout the world. The overall 5-year survival rate for lung cancer is dismal: 14% in the United States and even lower in other parts of the world. Recent developments in the armamentarium of chemotherapeutic agents for lung cancer have shown that two-drug combinations improve survival, relieve symptoms, and improve quality of life; however, complete response rates are still approximately 1% in stage IV disease and less than 20% of advanced stage patients survive 2 years. Therefore, improved therapeutic agents that increase efficacy are sorely needed. Most lung cancers overexpress thymidylate synthase and a variety of genes involved in cell cycle regulation. Previous studies have shown that some inhibitors of DNA synthesis (eg, gemcitabine) can improve the survival of advanced lung cancer patients, especially when combined with other agents such as cisplatin. The multitargeted antifolate, pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) was developed because it inhibits multiple enzymes involved in DNA synthesis including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase. The early studies of pemetrexed showed that the important dose-limiting toxicities were myelosuppression, mucositis, and diarrhea, all of which are common with any antimetabolite. Subsequent studies described in this article will show that these toxicities can be significantly reduced by the use of vitamin supplementation with folate and B12, and that pemetrexed has considerable activity in non-small cell lung cancer and mesothelioma.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Clinical Trials as Topic; Deoxycytidine; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Folic Acid; Gemcitabine; Glutamates; Guanine; Humans; Lung Neoplasms; Mesothelioma; Pemetrexed; Pleural Neoplasms; Thymidylate Synthase; Vitamin B 12

Topics: Adolescent; Adult; Age Factors; Child; Child, Preschool; Deglutition Disorders; Female; Ganglioneuroma; Horner Syndrome; Humans; Hypertension; Infant; Infant, Newborn; Lung Diseases; Lung Neoplasms; Male; Mediastinal Neoplasms; Mediastinum; Meningocele; Middle Aged; Neoplasm Regression, Spontaneous; Neoplasms, Nerve Tissue; Neurilemmoma; Neuroblastoma; Neurofibroma; Neurofibromatosis 1; Neurologic Manifestations; Osteoarthropathy, Secondary Hypertrophic; Pain; Paraganglioma, Extra-Adrenal; Pheochromocytoma; Sex Factors; Vitamin B 12

Topics: Aflatoxins; Airway Resistance; Animals; Anthracenes; Benzopyrenes; Cricetinae; Female; Heterocyclic Compounds; Humans; Hydrocarbons; Lactones; Lung Neoplasms; Male; Mice; Mouth Neoplasms; Naphthalenes; Nicotiana; Phenols; Plants, Toxic; Rats; Skin Neoplasms; Smoking; Stomach Neoplasms; Urinary Bladder Neoplasms; Vitamin B 12

To understand the relationship between response and survival in malignant pleural mesothelioma (MPM).. The original clinical trial was conducted from April 1999 through March 2001. Patients with epithelioid MPM (n=305) were categorized using modified pleural Response Evaluation Criteria in Solid Tumors by whether they responded to treatment. Median progression-free survival (PFS) and overall survival (OS) were estimated and hazard ratios for responders and nonresponders were estimated and compared using the log-rank test. Multivariable Cox proportional hazards models were used to adjust for baseline prognostic factors.. Patients who responded to frontline therapy had a significantly longer OS (hazard ratio, 0.34; 95% CI, 0.24-0.49; median, 20.6 months; 95% CI, 15.3 months to not reached) than did those who did not respond (median, 9.4 months; 95% CI, 8.1-11.0 months) (P<.001). Similarly, responders had a significantly longer PFS (hazard ratio, 0.50; 95% CI, 0.39-0.64; median, 7.8 months; 95% CI, 6.5-8.5 months) than did nonresponders (median, 3.7 months; 95% CI, 2.9-4.3 months) (P<.001). These results were confirmed when adjusting for baseline prognostic factors. We also observed a survival benefit associated with disease stabilization in MPM.. Our findings indicate that reduction in tumor burden or disease stabilization determined using modified pleural Response Evaluation Criteria in Solid Tumors is strongly associated with OS and PFS in epithelioid MPM.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Folic Acid; Humans; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Pemetrexed; Progression-Free Survival; Proportional Hazards Models; Tumor Burden; United States; Vitamin B 12; Vitamin B Complex

Pemetrexed is the preferred chemotherapeutic drug for nonsquamous, non-small-cell lung cancer patients whenever the predictive molecular biomarkers for targeted therapy have either not been assessed or are absent. As per manufacturers' instructions, supplementation with folic acid (FA; folate) at a dose of 350 to 1000 μg daily should be started seven days before the first dose of pemetrexed-based chemotherapy and continued during therapy and for 21 days after therapy cessation. Vitamin B

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Dietary Supplements; Female; Folic Acid; Humans; Lung Neoplasms; Male; Middle Aged; Patient Selection; Pemetrexed; Prospective Studies; Research Design; Treatment Outcome; Vitamin B 12; Young Adult

A vitamin B12 supplement is required in pemetrexed single agent therapy. Intramuscular administration is the method of choice; however, oral administration is simpler and easier and may be sufficiently effective. We conducted a Phase II study to evaluate the safety of oral administration of vitamin B12 in patients with advanced non-small cell lung cancer who received pemetrexed single agent therapy.. Folic acid and vitamin B12 were given orally for ˃ 1 week before pemetrexed administration. The primary end-point was onset of a grade ≥ 3 neutropenia ratio (50% of threshold expression ratios; an expectation expression ratio of 21%; α, 0.05; β, 0.1). Blood concentration of folic acid and homocysteine which are markers of vitamin B12 deficiency were also examined (UMIN000003180).. A total of 25 cases were registered from February 2010 to July 2014. The ratio of grade ≥ 3 neutropenia was 36% (95% CI 22-52 %). Grade ≥ 3 non-hematologic toxicity and hematologic toxicity were seen in 20% (5 cases) and 44% (11 cases) of patients, respectively. In addition, the homocysteine blood concentration just before the first cycle dosage of pemetrexed was significantly elevated relative to the 2-3 cycle.. This study failed to meet its primary endpoint. We could not demonstrate the safety and efficacy of the 1-week vitamin B12 oral administration protocol as compared with intramuscular administration.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Female; Folic Acid; Homocysteine; Humans; Lung Neoplasms; Male; Middle Aged; Pemetrexed; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

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

Prior supplementation with folic acid and vitamin B12 is required to reduce pemetrexed therapy toxicity; the recommended lead-in time is at least 7 days. On the basis of previous pharmacokinetic and clinical studies, we hypothesized that the lead-in time could be shortened to 24 hours, enabling earlier commencement of standard chemotherapy; thus, we planned the first prospective trial of this regimen.. Patients with advanced nonsquamous non-small cell lung cancer who had not previously received cytotoxic chemotherapy were enrolled. After measurement of homocysteine concentrations, the patients received 1,000 μg of vitamin B12 by intramuscular injection and began taking 350-500 μg of oral folic acid daily. Starting 24-48 hours after the vitamin B12 injection, the patients received intravenous 500 mg/m(2) pemetrexed and 75 mg/m(2) cisplatin for 4 cycles at 3 weekly intervals. The primary endpoint was the proportion of patients who developed neutropenia grade ≥3.. Thirty patients received chemotherapy starting within 48 hours of the vitamin B12 injection. No treatment-related deaths or grade 4 toxicity occurred. Neutropenia grade ≥3, other laboratory toxicities grade ≥3, and nonlaboratory toxicities grade ≥3 occurred in 6.7%, 13%, and 13% of patients, respectively. The baseline homocysteine concentrations were not higher in patients with grade ≥3 toxicities than in the remainder of the cohort (mean values, 8.6 and 10.7 μmol/L, respectively). The response rate to chemotherapy was 43%.. The shortened vitamin supplementation was well tolerated and retained antitumor efficacy. Analysis of baseline homocysteine concentrations confirmed the efficacy of short-term vitamin supplementation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Female; Folic Acid; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Middle Aged; Neutropenia; Pemetrexed; Prospective Studies; Treatment Outcome; Vitamin B 12

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

We examined the efficacy of enzastaurin plus pemetrexed as second-line therapy in patients with advanced (stage IIIA/B or IV) non-small cell lung cancer in a double-blinded, randomized, phase II study.. Patients received pemetrexed 500 mg/m intravenously on day 1 of 21-day cycles (day 8 in cycle 1) plus oral enzastaurin (250 mg two times per day; combination arm) or placebo (pemetrexed arm). Both arms received supplementation with vitamin B12, folic acid, and dexamethasone. An interim analysis was conducted to determine whether efficacy would warrant a phase III study.. The interim analysis showed no evidence of improved progression-free survival with enzastaurin. At final analysis (N = 160, 80 in each arm), baseline characteristics were well balanced. There was no significant difference in progression-free survival (3.0 months, p = 0.544) or overall survival (9.6 months in combination arm and 7.4 months in pemetrexed arm, p = 0.171). Drug-related serious adverse events included cerebrovascular accident, palpitations, and renal failure (n = 1, each) in combination arm and neutropenic sepsis, thrombocytopenia, and panniculitis (n = 1, each) in pemetrexed arm. Nonhematologic drug-related grade 3/4 toxicities were similar in both arms. Grade 3/4 hematologic toxicities were higher with the combination, specifically leukopenia (6.3% versus 0%), neutropenia (15.2% versus 5.0%), and thrombocytopenia (8.9% versus 1.3%). Of the 26 deaths reported on-study or within 30 days of discontinuation (10 in combination arm and 16 in pemetrexed arm), none were drug related.. The combination regimen of enzastaurin and pemetrexed is well tolerated but does not improve efficacy over pemetrexed and placebo as second-line treatment of unselected patients with advanced non-small cell lung cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Double-Blind Method; Female; Folic Acid; Glutamates; Guanine; Humans; Indoles; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Pemetrexed; Prognosis; Salvage Therapy; Survival Rate; Vitamin B 12

The objective of this study was to evaluate the efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B(12) in pretreated Japanese patients with advanced non-small cell lung cancer (NSCLC).. Patients with an Eastern Cooperative Oncology Group performance status 0 to 2, stage III or IV, and who received previously one or two chemotherapy regimens were randomized to receive 500 mg/m(2) pemetrexed (P500) or 1,000 mg/m(2) pemetrexed (P1000) on day 1 every 3 weeks. The primary endpoint was response rate.. Of the 216 patients evaluable for efficacy (108 in each arm), response rates were 18.5% (90% confidence interval, 12.6-25.8%) and 14.8% (90% confidence interval, 9.5-21.6%), median survival times were 16.0 and 12.6 months, 1-year survival rates were 59.2% and 53.7%, and median progression-free survival were 3.0 and 2.5 months for the P500 and P1000, respectively. Cox multiple regression analysis indicated that pemetrexed dose was not a significant prognostic factor. Drug-related toxicity was generally tolerable for both doses; however, the safety profile of P500 showed generally milder toxicity. Main adverse drug reactions of severity grade 3 or 4 were neutrophil count decreased (20.2%) and alanine aminotransferase (glutamine pyruvic transaminase) increased (15.8%) in P500 and neutrophil count decreased (24.3%), WBC count decreased (20.7%), and lymphocyte count decreased (18.0%) in P1000. One drug-related death from interstitial lung disease occurred in the P500.. P500 and P1000 are similarly active with promising efficacy and acceptable safety outcomes in pretreated patients with NSCLC. These results support the use of P500 as a second- and third-line treatment of NSCLC.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Female; Folic Acid; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Middle Aged; Pemetrexed; Regression Analysis; Safety; Treatment Outcome; Vitamin B 12

The purpose of this study was to investigate the utility of plasma pharmacokinetic and pharmacodynamic measures including plasma deoxynucleosides, homocysteine and methylmalonic acid concentrations in understanding the time course and extent of the inhibition of thymidylate synthase (TS) by pemetrexed in the context of a phase I/II combination study with vinorelbine. Eighteen patients received supplementation with folic acid and Vitamin B(12) 1 week before beginning treatment with pemetrexed and vinorelbine administered in a dose-escalating manner on a 21-day cycle. Heparinised blood samples were collected from consenting patients in the first cycle for pharmacokinetic analyses and in the first two cycles for determination of plasma thymidine, deoxyuridine, homocysteine and methylmalonic acid concentrations. These values were correlated with response and toxicity. Plasma deoxyuridine was used as a measure of TS inhibition, and concentrations of deoxyuridine were significantly elevated relative to baseline on days 1 (P<0.01), 2 (P<0.001) and 3 (P<0.05) after treatment at all pemetrexed dose levels (400-700 mg m(-2)). The magnitude of deoxyuridine elevation correlated with pemetrexed area under the plasma concentration-time curve (AUC) (r(2)=0.23, P<0.05). However, deoxyuridine concentrations returned to baseline between 8 and 15 days after treatment with pemetrexed, suggesting that inhibition of TS was not durable. Pemetrexed AUC correlated with the percentage decline (relative to baseline) in both platelets (r(2)=0.58, P<0.001) and leucocytes (r(2)=0.26, P<0.05) at day 8. Baseline homocysteine was also significantly correlated with these measures of haematological toxicity (r(2)=0.37, P<0.01 and r(2)=0.39, P<0.01, respectively). In addition, there was a significant reduction of plasma homocysteine on days 8 (P<0.005) and 15 (P<0.05) in cycle 1 compared to baseline values. The results suggest that the TS inhibitory effects of pemetrexed are short-lived and make the case for a more frequent schedule of administration such as every 2 weeks. The lack of protracted TS inhibition may be due to concomitant vitamin administration, and this may be the mechanism by which vitamins prevent life-threatening toxicity from pemetrexed. Baseline homocysteine concentration remains a predictive marker for haematological toxicity even following folate supplementation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Deoxyuridine; Dietary Supplements; Dose-Response Relationship, Drug; Female; Folic Acid; Glutamates; Guanine; Homocysteine; Humans; Lung Neoplasms; Male; Methylmalonic Acid; Middle Aged; Pemetrexed; Thymidine; Thymidylate Synthase; Vinblastine; Vinorelbine; Vitamin B 12

Pemetrexed and vinorelbine are active antineoplastic agents in non-small cell lung cancer (NSCLC). Phase I objectives include maximum tolerated dose (MTD) and recommended phase II dose determination, and pharmacokinetics of the pemetrexed-vinorelbine doublet in locally advanced or metastatic solid tumor patients (pts). Phase II objectives include tumor response evaluation, efficacy, and toxicity for first-line treatment of advanced NSCLC.. Phase I pts received pemetrexed (day 1, 300-700 mg/m2) and vinorelbine (days 1 and 8, 15-30 mg/m2) every 21 days. Pharmacokinetics determined at cycle 1. Beginning with dose-level 3, folic acid and Vitamin B12 supplementation were given.. Thirty-one phase I pts were enrolled. MTD was pemetrexed 700 mg/m2 and vinorelbine 30 mg/m2; and recommended phase II dose was pemetrexed 500 mg/m2 and vinorelbine 30 mg/m2. When administered in combination, pemetrexed and vinorelbine pharmacokinetics were consistent with single-agent administration. Thirty-seven (36 chemonaive) phase II NSCLC pts received pemetrexed-vinorelbine. Evaluable tumor response was 40%, with intent-to-treat 38%. One drug-related death occurred from febrile neutropenia with Staphylococcal infection. Grade 3/4 hematologic toxicities were neutropenia (65%) and febrile neutropenia (11%), while prevalent grade 3/4 non-hematologic toxicity was fatigue (27%).. The pemetrexed-vinorelbine combination is well tolerated and shows activity as first-line treatment in advanced NSCLC patients.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Creatinine; Dietary Supplements; Female; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Pemetrexed; Time Factors; Treatment Outcome; Vinblastine; Vinorelbine; Vitamin B 12

A nested case-control study was conducted within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort to test for associations between selected B-vitamins (folate, vitamin B(6), vitamin B(12)) and incident lung cancer. This trial was conducted in Finland between 1985 and 1993. Serum was analyzed for these nutrients and homocysteine among 300 lung cancer cases and matched controls (1:1). Odds ratios and 95% confidence intervals were determined in conditional and unconditional (controlling for the matching factors) logistic regression models, after adjusting for body mass index, years of smoking, and number of cigarettes smoked per day. No significant associations were seen between serum folate, vitamin B(12), or homocysteine and lung cancer risk. The authors found significantly lower risk of lung cancer among men who had higher serum vitamin B(6) levels. Compared with men with the lowest vitamin B(6) concentration, men in the fifth quintile had about one half of the risk of lung cancer (odds ratio = 0.51; 95% confidence interval: 0.23, 0.93; p-trend = 0.02). Adjusting for any of the other serum factors (folate, B(12), and homocysteine) either alone or jointly did not significantly alter these estimates. This is the first report from a prospectively conducted study to suggest a role for vitamin B(6) in lung cancer.

Topics: Age Distribution; Aged; Case-Control Studies; Cohort Studies; Confidence Intervals; Finland; Folic Acid; Homocysteine; Humans; Incidence; Lung Neoplasms; Male; Middle Aged; Odds Ratio; Pyridoxine; Reference Values; Risk Factors; Sampling Studies; Sensitivity and Specificity; Vitamin B 12

Serum folate and vitamin B12 levels were evaluated in 80 patients with small cell lung cancer at diagnosis and during therapy over a 30-week period. Approximately one half of the patients were randomized to receive hyperalimentation. Folate and vitamin B12 intake was adequate without parenteral nutrition in these cancer patients. Serum folate and Vitamin B12 levels did not correlate with disease extent. At the initiation of therapy, serum folate declined with increasing weight loss. During therapy, the intake of folate was adequate to maintain a normal serum folate despite marked weight loss.

Topics: Antineoplastic Combined Chemotherapy Protocols; Body Weight; Carcinoma, Small Cell; Energy Intake; Folic Acid; Humans; Lung Neoplasms; Parenteral Nutrition, Total; Random Allocation; Vitamin B 12

Tobacco smoking is a major known risk factor for lung cancer. While micronutrients, especially those involved in maintaining DNA integrity and regulating gene expression, may be protective, research on this association is limited. This report aimed to investigate associations of total folate, 5-methyltetrahydrofolate (5-mTHF) and vitamin B12 with incident risk of lung cancer, and whether the associations vary by smoking status. A nested case-control study with 490 incident lung cancer cases and 490 controls matched by age (±1 year), sex, residence, and center, drawn from a community-based prospective study in China, was conducted from 2016 to 2019. 5-mTHF accounted for the majority of total folate. Only 4.4% had detectable unmetabolized folic acid. Lung cancer cases had lower levels of 5-mTHF compared to controls. There was an inverse, nonlinear association between 5-mTHF and lung cancer, which persisted after adjustment for covariables (P for trend = .001). Compared to the lowest 5-mTHF quartile, those in higher quartiles had lower risks of lung cancer: second quartile OR = 0.65; 95% CI: 0.45-0.93; third quartile OR = 0.50; 95% CI: 0.34-0.74; fourth quartile OR = 0.56; 95% CI: 0.38-0.83. This inverse association was more pronounced among ever smokers; consistently, the highest risk of lung cancer (OR = 3.21, 95% CI: 1.97-5.24) was observed among ever smokers with low 5-mTHF levels compared to participants who never smoked and had higher 5-mTHF levels. Vitamin B12 was not associated with lung cancer risk. In this sample of Chinese adults without confounding by unmetabolized folic acid, higher levels of 5-mTHF were associated with lower risk of incident lung cancer.

Topics: Adult; Case-Control Studies; Folic Acid; Humans; Lung Neoplasms; Prospective Studies; Risk Factors; Vitamin B 12; Vitamins

Cobalt-mediated radical polymerization is noted for its great level of control over the polymerization of acrylic and vinyl esters monomers, even at high molar mass. Vitamin B

Topics: Biomarkers, Tumor; Bionics; Cobalt; Free Radicals; Humans; Lung; Lung Neoplasms; Multienzyme Complexes; Polymerization; Vitamin B 12; Vitamins

Since previous epidemiological studies reported inconsistent associations between dietary vitamin B12 intake and lung cancer risk, more studies are warranted to clarify this association in different populations.. The association between dietary B12 intake and lung cancer risk was examined in the Singapore Chinese Health Study, an ongoing prospective cohort study of 63 257 Singaporean Chinese men and women, 45-74 years of age at enrollment during 1993-1998 and were followed up for incidence of lung cancer for up to 25 years. Dietary vitamin B12 intake was derived from a validated food frequency questionnaire. Cox proportional hazard regression method was used to estimate hazard ratio and 95% confidence interval (CI) of lung cancer associated with dietary vitamin B12 intake with adjustment for multiple potential confounders.. After a mean follow-up of 17.64 years, 2001 study participants developed lung cancer. High levels of vitamin B12 intake were associated with significantly increased risk of lung cancer (Ptrend = 0.03). Compared with the lowest quintile, hazard ratios (95% CIs) of lung cancer for quintile 2, 3, 4, and 5 of vitamin B12 intake were 1.09 (0.95-1.25), 1.11 (0.96-1.28), 1.11 (0.97-1.29) and 1.18 (1.03-1.35), respectively. This positive association was more apparent in men than in women, in adenocarcinoma patients, or in participants with equal or less than 2 years follow-up than those with longer duration of follow-up.. Higher intake of dietary vitamin B12 was associated with increased risk of lung cancer. This highlights the potential harmful effect of vitamin B12 supplementation for lung cancer.

Topics: Diet; Female; Humans; Lung Neoplasms; Male; Prospective Studies; Risk Factors; Vitamin B 12

Dietary methyl-donors play important roles in physiological processes catalyzed by B vitamins as coenzymes, and are used for complementary support in oncotherapy. Our hypothesis was that methyl-donors can not only assist in tolerating cancer treatment but may also directly interfere with tumor growth and proliferation. Therefore, we investigated the proposed cancer inhibitory effects of methyl-donors (in a mixture of L-methionine, choline chloride, folic acid, and vitamin B12) on MCF7 and T47D breast cancer as well as A549 and H1650 lung cancer cell lines. Indeed, methyl-donor treatment significantly reduced the proliferation in all cell lines, possibly through the downregulation of MAPK/ERK and AKT signaling. These were accompanied by the upregulation of the pro-apoptotic Bak and Bax, both in MCF7 and H1650 cells, at reduced anti-apoptotic Mcl-1 and Bcl-2 levels in MCF7 and H1650 cells, respectively. The treatment-induced downregulation of p-p53(Thr55) was likely to contribute to protecting the nuclear localization and apoptosis inducing functions of p53. The presented features are known to improve the sensitivity of cancer therapy. Therefore, these data support the hypothesis, i.e., that methyl-donors may promote apoptotic signaling by protecting p53 functions through downregulating both the MAPK/ERK and the AKT pathways both in breast and lung adenocarcinoma cell lines. Our results can emphasize the importance and benefits of the appropriate dietary supports in cancer treatments. However, further studies are required to confirm these effects without any adverse outcome in clinical settings.

Topics: Apoptosis; Breast; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Choline; Folic Acid; Humans; Lung; Lung Neoplasms; MAP Kinase Signaling System; Methionine; Methylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Vitamin B 12

Cognitive dysfunction has a negative effect on cancer treatment; however, in a cancer setting, specific treatments can restore cognitive function. Such conditions are known as reversible dementia, with one of these being vitamin B12 (VB12) deficiency. However, there have been no reports of VB12 deficiency identified by preoperative evaluation in cancer patients.. We studied a patient who was referred to the Department of Psycho-oncology on suspicion of cognitive decline prior to lung cancer surgery. Preoperative evaluation revealed VB12 deficiency.. The patient was an 82-year-old woman diagnosed with lung cancer. She also presented with cognitive decline and, therefore, was referred to the Department of Psycho-oncology for preoperative evaluation. The patient scored 19 points on a Mini-Mental State Examination (MMSE), which is indicative of cognitive decline. As the onset of symptoms occurred several months previously and they were subacute, the possibility of reversible dementia was considered. Extensive examination revealed VB12 deficiency, and VB12 replacement therapy normalized the MMSE score to 25 points before surgery.. When cognitive decline is observed in cancer patients, it is necessary to actively evaluate the serum levels of some B vitamins, including VB12.

Topics: Aged, 80 and over; Cognitive Dysfunction; Dementia; Female; Humans; Lung Neoplasms; Vitamin B 12; Vitamin B 12 Deficiency

High cobalamin levels have previously been associated with short-term cancer risk, including lung cancer. We explored whether levels of cobalamin and/or its binding proteins are useful as a diagnostic tool in patients suspected of non-small cell lung cancer. We included 889 patients referred for fast-track diagnosis of lung cancer to Aarhus University Hospital, Denmark. We analyzed plasma concentrations of cobalamin, transcobalamin, holotranscobalamin and haptocorrin. Information on lung cancer diagnosis was retrieved from a national database. The study cohort showed levels above reference intervals for cobalamin 12%, holotranscobalamin 25%, transcobalamin 9% and haptocorrin 36% (all

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Odds Ratio; ROC Curve; Transcobalamins; Vitamin B 12; Young Adult

Vitamin supplementation reduces pemetrexed toxicity. Raised plasma homocysteine reflects deficiency in vitamin B12 and folate, and is suppressed by supplementation. This observational study of 112 patients receiving pemetrexed-based chemotherapy assessed homocysteine levels after 3 weeks of vitamin supplementation, hypothesising high levels would correlate with ongoing deficiency, thus increased toxicity.. Primary endpoint was the composite of proportion of patients with treatment delay/ dose reduction/ drug change or hospitalisation during the first six weeks of chemotherapy, comparing those with normal plasma homocysteine (successfully supplemented, SS) and those with high homocysteine (unsuccessfully supplemented, USS). Secondary endpoints included toxicity and analyses for depression. Post-hoc analysis examined correlation between interval of vitamin and folate supplementation and pemetrexed on primary endpoint and grade 3-4 toxicities.. Eighty-four patients (84%) were successfully supplemented (SS group). The proportion of patients undergoing a treatment delay/ dose reduction/ drug change or hospitalisation in SS group was 44.0% (95% confidence interval [CI] 33.2%-55.3%) and in USS group was 18.8% (95% CI 4.0%-45.6%) (p = 0.09). Twelve percent of patients gave a past history of depression however 66% of patients had an on study Hospital Anxiety and Depression (HAD) score of >7. Supplementation status was not associated with depression. The median overall survival (OS) was 11.8 months (95% CI 8.6-16.5) in the SS group and 8.8 months (95% CI 6.6-16.2) in the US group (p = 0.5). The number of days (<7 or ≥ 7 days) between vitamin B12 and folate initiation and pemetrexed administration, had no effect on the primary endpoint and grade 3-4 toxicities.. On-treatment homocysteine levels were not a biomarker of toxicity or depression. Standard vitamin supplementation is adequate in the majority of patients receiving pemetrexed. High HAD score were noted in this population giving an opportunity for mental health intervention. The lead-in time for vitamin supplementation can be short.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Carcinoma, Non-Small-Cell Lung; Depression; Dietary Supplements; Female; Folic Acid; Homocysteine; Humans; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Pemetrexed; Prospective Studies; Treatment Outcome; Vitamin B 12; Vitamins

The administration of pemetrexed requires routine supplementation with vitamin B12 and folate, even if blood concentrations are normal, in order to mitigate its hematologic toxicity. Emerging data suggest that such premedication can be initiated less than 1 week before starting chemotherapy. The current available data on later administration of vitamin B12 in patients with thoracic tumors are placed into a general context, and the possible role of such strategy in the era of immunooncology is discussed.

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Pemetrexed; Thoracic Neoplasms; Vitamin B 12

Administration of vitamin B12 and folic acid for 7 days prior to the administration of the first dose of pemetrexed is recommended. However, vitamin supplementation rarely is initiated less than 7 days prior to the first dose of pemetrexed. Therefore, we analyzed the safety of pemetrexed with vitamin supplementation for less than 7 days prior to the first dose of pemetrexed.. Patients were classified into 2 groups according to the duration of vitamin supplementation prior to the first dose of pemetrexed: group A received vitamin supplementation for 7 days or more, and group B received vitamin supplementation for less than 7 days. We analyzed adverse effects, such as myelosuppression, rash, and diarrhea, after 1 cycle of pemetrexed therapy.. A total of 70 patients were administered pemetrexed; 40 patients were men and 30 were women with a median age of 64.5 years(range, 43-86 years). A total of 57 patients were classified into group A and 13 into group B; 33 patients were administered pemetrexed as a first-line treatment. Neutropenia of Grade 3 or more was observed in 4/49(8.2%)patients in group A and 2/13(15.4%)patients in group B(p=0.60). There were no significant differences in the rates of occurrence of neutropenia, rash, and diarrhea.. This retrospective study indicated that patients could be safely treated with pemetrexed if vitamin supplementation is initiated for less than 7 days prior to the first administration of pemetrexed. However, further studies are needed because of a lack of statistical power and adjustment for confounding factors.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Diarrhea; Dietary Supplements; Drug Combinations; Exanthema; Female; Folic Acid; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Middle Aged; Neutropenia; Pemetrexed; Retrospective Studies; Vitamin B 12

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Folic Acid; Humans; Lung Neoplasms; Male; Vitamin B 12

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Folic Acid; Humans; Lung Neoplasms; Male; 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

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

Pemetrexed (MTA) is a multitargeted antifolate drug approved for lung cancer therapy. Clinically, supplementation with high doses of folic acid (FA) and vitamin B12 (VB12) lowers MTA cytotoxicities. An antagonistic effect of FA/VB12 on MTA efficacy has been proposed. However, patients who receive FA/VB12 show better tolerance to MTA with improved survival. The aims of this study are to investigate the modulation of FA and VB12 on MTA drug efficacy in human nonsmall cell lung cancer (NSCLC) cell lines. The sensitivities of cells, apoptosis, and MTA-regulated proteins were characterized to determine the possible effects of high doses of FA and VB12 on MTA efficacy. MTA has the lowest efficacy under 10% serum conditions. However, supplementation with FA and VB12 individually and additively reversed the insensitivity of NSCLC cells to MTA treatment with 10% serum. The enhanced sensitivities of cells following FA/VB12 treatment were correlated with increasing apoptosis and were specific to MTA but not to 5-fluorouracil (5-FU). Enhanced sensitivity was also associated with p21(WAF1/Cip1) expression level. Our results revealed no antagonistic effect of high doses of FA/VB12 on MTA efficacy in cancer cells grown in nutrient medium. Furthermore, these data may partially explain why supplementation of FA and VB12 resulted in better survival in MTA-treated patients.

Topics: Antimetabolites, Antineoplastic; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Dietary Supplements; Drug Screening Assays, Antitumor; Fluorouracil; Folic Acid; Folic Acid Antagonists; G1 Phase; Glutamates; Guanine; Humans; Lung Neoplasms; Neoplasm Proteins; Pemetrexed; Protein Stability; Serum; Treatment Outcome; Vitamin B 12

Circulating unconjugated bilirubin (UCB) has been reported to protect against lung and colorectal cancer. The present study aimed to explore, for the first time, whether mildly elevated circulating UCB, as found in Gilbert`s syndrome (GS), is associated with changes of DNA damage. A random 76 individuals, matched for age and gender, were recruited from the general population and allocated into the GS group (UCB ≥ 17.1 µM; n = 38) or control group (UCB <17.1 µM; n = 38). Chromosomal and cytological changes were determined in lymphocytes and buccal cells using the cytokinesis-block micronucleus cytome assay (CBMN) and buccal micronucleus cytome assay (BMcyt). No significant differences were found between GS subjects and the control group in the CBMN and BMcyt determined endpoints. Subsequently, when age dependency of effects were analysed, lower formation of buccal micronucleated cells (by 73.3%) and buccal nuclear buds (by 70.9%) in the GS subgroup ≥ 30 years were found, compared to the GS subgroup <30 years. These findings suggest DNA protection in epithelial tissue of older individuals with GS.

Topics: Adult; Aged; Aged, 80 and over; Bilirubin; Chromosome Aberrations; Colorectal Neoplasms; Comet Assay; Cytokinesis; DNA Damage; Endpoint Determination; Female; Folic Acid; Gilbert Disease; Homocysteine; Humans; Lung Neoplasms; Lymphocytes; Male; Micronucleus Tests; Middle Aged; Vitamin B 12; Young Adult

Aberrant DNA methylation is a major epigenetic mechanism of gene silencing in a wide range of human cancers. Previous studies on DNA methylation typically used paired tumor and normal-appearing surrounding tissues from cancer-bearing individuals. However, genomic DNA isolated from surrogate tissues such as blood cells represents an attractive material that can be exploited in the discovery of biomarkers of exposure and tumorigenesis. Here we examined the association between lung cancer and DNA methylation patterns in a panel of candidate genes. We also investigated whether blood levels of vitamin metabolites modify DNA methylation levels in blood cells. To this end, we quantitatively determined DNA methylation levels in blood cells of nested cases and controls from a prospective study with well defined dietary habits and lifestyles. Multiple CpG sites in five genes (CDKN2A/p16, RASSF1A, GSTP1, MTHFR, and MGMT) that are frequent targets of hypermethylation in a variety of human malignancies were included in the analysis. While no clear association between DNA methylation patterns and the case/control status was found, with the exception of RASSF1A hypermethylation, methylation level changed according to serum levels of 1-carbon metabolites and vitamins B. Overall, folate was associated with increased methylation levels of RASSF1A and MTHFR and methionine was associated with decreased methylation levels of RASSF1A. The associations with folate were more pronounced among never smokers while the associations with methionine were more evident among ever-smokers. These results are consistent with the notion that blood levels of 1-carbon metabolism markers and dietary/lifestyle factors may modify DNA methylation levels in blood cells and that blood cells can be exploited for the discovery of epigenetic biomarkers of exposures, providing proof-of-principle on the use of blood samples in the context of prospective studies.

Topics: Biomarkers, Tumor; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Epigenesis, Genetic; Female; Genes, p16; Glutathione S-Transferase pi; Humans; Lung Neoplasms; Male; Middle Aged; Prospective Studies; Riboflavin; Risk Factors; Tumor Suppressor Proteins; Vitamin B 12; Vitamin B 6; Vitamins

A water soluble vitamin B(12)-rhenium conjugate was synthesized and used in concert with intrinsic factor to screen for cubilin receptor-mediated uptake in lung cancer cells. Internalization of the conjugate demonstrated that it could be used to rapidly screen for the cubilin receptor in living cells, subsequently confirmed with Western blotting and RT-PCR.

Topics: Biological Transport; Cell Line, Tumor; Fluorescent Dyes; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Receptors, Cell Surface; Rhenium; Solubility; Vitamin B 12; Water

We investigated whether fluorescent agents, especially vitamin B2, can act as tracers for intraoperative pulmonary sentinel node mapping.. Vitamin B2, fluorescent beads, and green fluorescent protein (GFP) were each injected into pulmonary parenchyma in 4 pigs (experiment 1). The safety of each tracer was also verified in 12 rats (experiment 2).. Experiment 1: In all groups, the sentinel lymph node was identified in 3 out of the 4 pigs (75%). Speed of agent dispersion: vitamin B2>GFP >fluorescent beads. Level of fluorescence judged as: vitamin B2>GFP=fluorescent beads. Experiment 2: In all groups, all rats survived until sacrifice without complications. In the fluorescent beads group, the fluorescent beads remained in the blood vessels.. Vitamin B2 is inexpensive, safe and easy to apply. It is anticipated that clinical application of vitamin B2 for intraoperative pulmonary sentinel node mapping will become possible.

Topics: Animals; Female; Fluorescent Dyes; Green Fluorescent Proteins; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Microspheres; Rats; Rats, Wistar; Sentinel Lymph Node Biopsy; Swine; Vitamin B 12

Topics: Antioxidants; Ascorbic Acid; beta Carotene; Colorectal Neoplasms; Confounding Factors, Epidemiologic; Dietary Supplements; Female; Folic Acid; Humans; Incidence; Lung Neoplasms; Male; Neoplasms; Primary Prevention; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Risk Assessment; Selenium; United States; Vitamin B 12; Vitamin B 6; Vitamin E

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

Pemetrexed is a multitargeted antifolate initially approved as a single agent for the second-line treatment of locally advanced or metastatic non-small cell lung cancer and more recently in the first-line setting combined with cisplatin. The combination of pemetrexed with carboplatin has been tested in several phase II clinical trials showing interesting antitumour activity with mild toxicity. Supplementation with folic acid and vitamin B12 during treatment with pemetrexed is recommended to reduce potential haematological and gastrointestinal adverse events.. A patient experienced cutaneous lesions including widespread erythema, epidermal detachment, and skin denudation, associated with deterioration of his general condition after the second cycle of this chemotherapy combination, which was clinically and histologically compatible with toxic epidermal necrolysis (Lyell's syndrome). Treatment with systemic steroids, antihistamines, and antibiotics led to resolution of the skin lesions and improvement of his general condition.. To our knowledge, this is the second case reported in the literature of this type of suspected adverse drug reaction associated with a pemetrexed-based chemotherapy combination.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Folic Acid; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Middle Aged; Pemetrexed; Stevens-Johnson Syndrome; Vitamin B 12

The main objective of this study was to evaluate the safety of second-line pemetrexed in Stage IIIB or IV NSCLC.. Overall, 95 patients received pemetrexed 500 mg/m2 i.v. over Day 1 of a 21-day cycle. Patients also received oral dexamethasone, oral folic acid and i.m. vitamin B12 supplementation to reduce toxicity. NCI CTC 2.0 was used to rate toxicity. All the adverse events were graded in terms of severity and relation to study treatment. Dose was reduced in case of toxicity and treatment was delayed for up to 42 days from Day 1 of any cycle to allow recovering from study drug-related toxicities. Tumor response was measured using the RECIST criteria.. Patients received a median number of 4 cycles and 97.8% of the planned dose. Overall, 75 patients (78.9% of treated) reported at least one adverse event: 34 (35.8%) had grade 3 as worst grade and only 5 (5.2%) had grade 4. Drug-related events occurred in 57.9% of patients. Neutropenia (8.4%) and leukopenia (6.3 %) were the most common grade 3/4 hematological toxicities. Grade 3 anemia and thrombocytopenia were reported in 3.2% and 2.1% of patients, respectively. Diarrhea (6.3%), fatigue (3.2%) and dyspnea (3.2%) were the most common grade 3/4 non-hematological toxicities. The most common drug-related toxicities (any grade) were pyrexia (11.6%), vomiting, nausea, diarrhea and asthenia (9.5%) and fatigue (8.4%). Tumor Response Rate (CR/PR) in treated patients was 9.2%. The survival at 4.5 months (median follow-up) was 79% and the median PFS was 3.1 months. Twenty patients (21.1%) died mainly because of disease progression.. Patients with locally advanced or metastatic NSCLC could benefit from second-line pemetrexed, with a low incidence of hematological and non-hematological toxicities.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Dexamethasone; Female; Folic Acid; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pemetrexed; Vitamin B 12

Generalized pruritus can often be the primary manifestation of systemic disease.. To determine how frequently generalized pruritus had a systemic etiology in an outpatient population seen in a dermatology department and whether any identifiable patient characteristics meant a systemic explanation of generalized pruritus was more likely.. A prospective controlled study of 55 patients with generalized pruritus and 41 healthy age- and sex-matched control subjects. Clinical data were collected from patients and laboratory parameters investigated in both patients and healthy control subjects to determine the frequency of systemic disease in each group.. Of 55 patients, 12 had a systemic cause of pruritus. Pruritus was the initial symptom of systemic disease in eight of these patients. The underlying diseases included hypothyroidism, chronic lymphocytic leukemia, hepatitis C, hepatitis B, diabetes mellitus, lung cancer, uremia, and iron deficiency anemia. Of these, iron deficiency anemia was the most common cause. Compared with the control group, mean serum hemoglobin, iron, and cyanocobalamin (vitamin B(12)) levels in patients with generalized pruritus were lower. No other patient characteristics were statistically associated with systemic causes of pruritus.. Generalized pruritus was the initial symptom of a systemic disease in 8 of 55 patients presenting to a dermatology outpatient clinic with this complaint. A number of underlying diseases were identified, of which the most common was iron deficiency anemia.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Iron-Deficiency; Case-Control Studies; Diabetes Complications; Female; Hemoglobins; Hepatitis, Viral, Human; Humans; Hypothyroidism; Iron; Leukemia, Lymphocytic, Chronic, B-Cell; Lung Neoplasms; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms; Pruritus; Statistics, Nonparametric; Uremia; Vitamin B 12

Treatment with third-generation chemotherapy agents improves survival and quality of life of patients with non-small-cell lung cancer (NSCLC). Despite these favorable outcomes, most patients receiving front-line therapy experience disease progression. The availability of many new novel agents with activity in NSCLC has prompted investigators to explore second-line chemotherapy options. For many years, docetaxel was the only approved agent for the second-line treatment of NSCLC. More recently, the multi-targeted antifolate pemetrexed has demonstrated activity in patients previously treated with chemotherapy with locally advanced or metastatic NSCLC. The findings of a phase III trial comparing pemetrexed to docetaxel led to the regulatory approval of pemetrexed as monotherapy for the second-line treatment of NSCLC. Several other novel therapies, including molecular targeting agents such as erlotinib, are under development in clinical trials in patients with NSCLC. One of these trials has subsequently led to the approval of erlotinib as second- or third-line therapy in advanced NSCLC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Docetaxel; Folic Acid Antagonists; Glutamates; Guanine; Humans; Lung Neoplasms; Pemetrexed; Salvage Therapy; Survival Analysis; Taxoids; Vitamin B 12

Pemetrexed is a new cytotoxic agent that is a standard of care for the second-line treatment of non-small-cell lung cancer (NSCLC) and treatment of malignant pleural mesothelioma. It is currently in clinical development for the first-line treatment of NSCLC. In untreated advanced NSCLC, single-agent activity has been demonstrated in phase II trials. Pemetrexed has encouraging response rates and a favorable toxicity profile. Pemetrexed also has promising activity and acceptable toxicity when combined with platinum compounds or gemcitabine. Dietary supplementation with low-dose folic acid and vitamin B(12) significantly reduces the incidence and severity of toxicities without compromising the antitumor activity of pemetrexed. With its innovative mode of action, proven efficacy, favorable toxicity profile and convenient administration, pemetrexed represents a new therapeutic option for the treatment of advanced NSCLC.

Topics: Antimetabolites, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Dietary Supplements; Folic Acid; Folic Acid Antagonists; Glutamates; Guanine; Humans; Lung Neoplasms; Pemetrexed; Vitamin B 12

We measured the concentrations of folate and vitamin B-12 in paired tissue samples of squamous cell cancer (SCC) and adjacent grossly normal-appearing uninvolved bronchial mucosa (from which SCC developed and also "at risk" of developing SCC) of the lung in 12 subjects to determine the involvement of these vitamins in 1) lung carcinogenesis and 2) global DNA methylation. The folate concentrations were significantly lower in SCCs than in uninvolved tissues (p = 0.03). The vitamin B-12 concentrations were also significantly lower in SCCs than in uninvolved tissues (p = 0.02). The radiolabeled methyl incorporation (inversely related to the degree of in vivo DNA methylation) was significantly higher in SCCs than in uninvolved tissues (p < 0.0001). The correlation between folate and radiolabeled methyl incorporation was inverse and statistically significant in SCCs (p = 0.03). The correlation between vitamin B-12 and radiolabeled methyl incorporation also was inverse and statistically significant in SCCs (p = 0.009). The relationship between tissue vitamin B-12 and DNA methylation was minimal in uninvolved tissues. The relationship between folate and DNA methylation, however, was inverse in uninvolved tissues. In the multiple regression models that included both vitamins, only folate was inversely associated with radiolabeled methyl incorporation in uninvolved and cancerous tissues. These results suggested that folate might be the limiting vitamin for proper DNA methylation in SCC as well as in tissues at risk of developing SCC. Several possible mechanisms of folate deficiency, including inactivation of the vitamin by exposure to carcinogens of cigarette smoke and underexpression or absence of folate receptor in SCCs and associated premalignant lesions, are discussed in light of these findings.

Topics: Aged; Aged, 80 and over; Carcinoma, Squamous Cell; DNA Methylation; Folic Acid; Folic Acid Deficiency; Humans; Lung Neoplasms; Middle Aged; Smoking; Statistics as Topic; Vitamin B 12; Vitamin B 12 Deficiency

The purpose of our study was to evaluate the effects of cigarette smoking and serum lipids, folate, and vitamin B12 on the development of lung cancer in the Turkish population. The study group consisted of patients with histologically proven lung cancer and the control group comprised healthy smokers being followed in our smoking cessation outpatient department. Smoking history was obtained from all subjects and serum total cholesterol, HDL cholesterol, triglycerides, vitamin B12, and folate levels were measured. Pack/years of cigarettes smoked were significantly higher in the subjects with lung cancer than in the control group (p < 0.01). Serum total cholesterol, HDL cholesterol, triglyceride, serum folate, and vitamin B12 levels were within normal limits in both groups (p < 0.05), but serum vitamin B12 levels were statistically significantly higher (p < 0.01) in the cancer group than in the controls. In our study, we did not observe low levels of serum cholesterol, vitamin B12, or folate in the lung cancer patients.

Topics: Adolescent; Adult; Aged; Cholesterol; Female; Folic Acid; Humans; Lipids; Lipoproteins, HDL; Lung Neoplasms; Male; Middle Aged; Nicotiana; Plants, Toxic; Smoking; Time Factors; Triglycerides; Turkey; Vitamin B 12

Topics: Blood Proteins; Carcinoma, Bronchogenic; Chromatography, Gel; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Protein Binding; Saliva; Transcobalamins; 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

Topics: Adrenal Gland Neoplasms; Adult; Binding Sites; Cells, Cultured; Centrifugation; Cobalt Radioisotopes; Dialysis; Female; Granulocytes; Hodgkin Disease; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Leukocytes; Lung Neoplasms; Male; Melanoma; Multiple Myeloma; Protein Binding; Proteinuria; Pyelonephritis; Time Factors; Vitamin B 12

Topics: Adult; Carcinoma, Bronchogenic; Diagnosis, Differential; Humans; Leukemia, Myeloid; Leukemoid Reaction; Lung Neoplasms; Male; Protein Binding; Vitamin B 12

Topics: Adult; Age Factors; Aged; Cyclophosphamide; Female; Humans; Injections, Intravenous; Intestinal Absorption; Intestine, Small; Intrinsic Factor; Lung Neoplasms; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Ovarian Neoplasms; Sex Factors; Stomach Neoplasms; Vitamin B 12; Xylose

Topics: Animals; Lung Neoplasms; Lymphatic Metastasis; Melphalan; Neoplasm Metastasis; Neoplasm Transplantation; Rats; Sarcoma, Experimental; Tail; Thiotepa; Vitamin B 12

Topics: Appetite; Body Weight; Cobalt; Copper; Corrinoids; Drug Synergism; Drug Therapy; Geriatrics; Hematopoiesis; Humans; Iron; Liver Extracts; Lung Neoplasms; Lysine; Manganese; Tissue Extracts; Tuberculosis; Tuberculosis, Pulmonary; Vitamin B 12; Vitamin B Complex