Phase I Clinical and Pharmacogenetic Trial of Irinotecan and Raltitrexed Administered Every 21 Days to Patients With Cancer

2001 ◽  
Vol 19 (20) ◽  
pp. 4081-4087 ◽  
Author(s):  
James P. Stevenson ◽  
Maryann Redlinger ◽  
Leo A.J. Kluijtmans ◽  
Weijing Sun ◽  
Kenneth Algazy ◽  
...  
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Clinical Investigation ◽  
Performance Status ◽  
Mthfr C677t ◽  
Mthfr Gene ◽  
Plasma Homocysteine ◽  
Gastrointestinal Malignancies ◽  
Patients With Cancer ◽  
Functional Polymorphisms

PURPOSE: Irinotecan and raltitrexed display schedule-dependent synergy in vitro, which supports the clinical investigation of the combination. Functional polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene result in intracellular redistribution of folate derivatives, which may affect raltitrexed-associated cytotoxicity.PATIENTS AND METHODS: Patients with a range of solid cancers and good performance status received irinotecan as a 90-minute infusion on day 1 and raltitrexed as a 15-minute infusion on day 2, repeated every 21 days. Samples were collected for MTHFR C677T genotyping and fasting plasma homocysteine during the first cycle.RESULTS: Thirty-nine assessable patients received 127 cycles of therapy. Irinotecan doses ranged from 100 to 350 mg/m2, and raltitrexed, 1.0 to 4.0 mg/m2. Raltitrexed doses of more than 3.0 mg/m2were not tolerated and were associated with dose-limiting asthenia, diarrhea, and AST/ALT elevation. Irinotecan/raltitrexed doses of 350/3.0 mg/m2were well-tolerated; principal toxicities included neutropenia, diarrhea, and fatigue. Two partial responses were observed in patients with pretreated gastroesophageal cancers. Homozygotes with the MTHFR 677 TT polymorphism incurred significantly less raltitrexed-associated toxicity than those with either wild-type or heterozygous genotypes (P = .05). No significant differences were noted in plasma homocysteine values between the genotypic subtypes, and plasma homocysteine levels did not predict the risk of toxicity.CONCLUSION: Irinotecan and raltitrexed doses of 350 and 3.0 mg/m2are recommended for further study on a day 1, 2 schedule every 21 days. Efficacy results suggest that trials in upper and lower gastrointestinal malignancies are warranted. MTHFR C677T genotypes may be predictive of clinical raltitrexed toxicity.

Methylenetetrahydrofolate reductase polymorphisms as risk factors for retinal venous occlusive disease: A literature review

2021 ◽  
pp. 112067212110006
Author(s):  
Manuel Marques ◽  
Francisco Alves ◽  
Miguel Leitão ◽  
Catarina Rodrigues ◽  
Joana Tavares Ferreira
Keyword(s):  
Risk Factors ◽  
Literature Review ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr C677t ◽  
Mthfr Gene ◽  
Mthfr Polymorphisms ◽  
Vein Occlusion ◽  
C677t Mutation ◽  
Retinal Vascular Disease

The role of polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene in retinal vein occlusion (RVO) is a theme of discussion since the first reports of RVO in patients with MTHFR C677T mutation and without classic acquired risk factors for retinal vascular disease. The association between MTHFR polymorphisms and RVO has been studied over the last 20 years producing conflicting results. This review aims to summarize the literature concerning the role MTHFR polymorphisms as risk factors for RVO.

scholarly journals B-vitamins, homocysteine metabolism and CVD

2004 ◽  
Vol 63 (4) ◽  
pp. 597-603 ◽  
Author(s):  
J. J. Strain ◽  
L. Dowey ◽  
M. Ward ◽  
K. Pentieva ◽  
H. McNulty
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Independent Predictor ◽  
Systemic Disease ◽  
Plasma Concentrations ◽  
Nutrient Status ◽  
Mthfr Gene ◽  
Plasma Homocysteine ◽  
B Vitamins ◽  
Vitamin B ◽  
Pathophysiological Mechanism

The present review focuses on the B-vitamins, i.e. folate, vitamin B12, vitamin B6and riboflavin, that are involved in homocysteine metabolism. Homocysteine is a S-containing amino acid and its plasma concentrations can be raised by various constitutive, genetic and lifestyle factors, by inadequate nutrient status and as a result of systemic disease and various drugs. Hyperhomocysteinaemia is a modest independent predictor of CVD and stroke, but causality and the precise pathophysiological mechanism(s) of homocysteine action remain unproven. The predominant nutritional cause of raised plasma homocysteine in most healthy populations is folate insufficiency. Vitamin B12and, to a lesser extent, vitamin B6are also effective at lowering plasma homocysteine, especially after homocysteine lowering by folic acid in those individuals presenting with raised plasma homocysteine. However, riboflavin supplementation appears to be effective at lowering plasma homocysteine only in those individuals homozygous for the T allele of the C677 T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. This gene codes for the MTHFR enzyme that produces methyltetrahydrofolate, which, in turn, is a substrate for the remethylation of homocysteine by the vitamin B12-dependent enzyme methionine synthase. Individuals with the MTHFR 677 TT genotype are genetically predisposed to elevated plasma homocysteine, and in most populations have a markedly higher risk of CVD.

A case-control study investigating the effect of MTHFR C677T variant on performance of elite athletes

2020 ◽  
Vol 20 ◽  
Author(s):  
Ayse Feyda Nursal ◽  
Serbulent Yigit ◽  
Husniye Rustemoglu ◽  
Abdullah Cenikli
Keyword(s):  
Athletic Performance ◽  
Methylenetetrahydrofolate Reductase ◽  
Elite Athletes ◽  
Mthfr C677t ◽  
Mthfr Gene ◽  
Control Group ◽  
Genotype Distribution ◽  
Significant Difference ◽  
Pcr Rflp ◽  
Strength Of Association

Objective: Increased level of plasma homocysteine (Hcy) is a potential risk factor for several multi-system diseases. The Methylenetetrahydrofolate reductase (MTHFR) gene C677T variant has been established as an important genetic determinant of hyperhomocysteinemia. There are conflicting reports about the effects of physical activity on plasma Hcy. Therefore, the main aim of this study was to investigate whether the MTHFR C677T variant affects the elite athletic performance. Methods: This study was carried out on 214 individuals (114 elite athletes and 100 sedentary controls). Genotyping was performed using PCR- RFLP method. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. Results: There was a significant difference between the athletes and the control group in genotype distribution and allele frequency of the MTHFR C677T variant. MTHFR C677T CC genotype and C allele were more prevalent in elite athletes than those in the sedentary controls (p =0.007, OR: 2.16, 95%:1.26-3.70; p=0.009, OR: 1.84, 95%:1.18-2.89, respectively). The control group had a higher MTHFR C677T CT genotype than the athletes had (p=0.019, OR: 0.51, 95%:0.30-0.88). There was no deviation from HWE for the MTHFR C677T variant in the groups. Conclusion: Our findings support that there is an association between the MTHFR C677T C allele and athletic performance among the elite Turkish athletes.

TS and MTHFR gene polymorphisms in patients (pts) with recurrent or metastatic squamous cell carcinoma of the head or neck (SCCHN) treated with pemetrexed (P) and bevacizumab (B)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e17011-e17011
Author(s):  
M. Romkes ◽  
T. M. Feinstein ◽  
S. Zhong ◽  
S. Buch ◽  
M. K. Gibson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr C677t ◽  
Mthfr Gene ◽  
Trend Test ◽  
Sequence Detection ◽  
Mthfr Polymorphism ◽  
Detection Systems ◽  
Pcr Product ◽  
Significant Difference

e17011 Background: P inhibits multiple enzymes in folate metabolism. We examined polymorphisms in thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) in patients with SCCHN treated in a phase II clinical trial with P and B (ASCO 2008; A6069). Methods: All pts were treated with P 500 mg/m2 and B 15 mg/kg, given IV every 21 days until progression. Primary endpoint was time to progression (TTP). DNA was isolated from whole blood samples using commercially available kits. Polymorphisms examined were MTHFR (C677T, A1298C and G1793A) and TS (TS2R3R, TSG2RG and TSmut6). The MTHFR SNPs were detected using TaqMan based SNP genotyping kits from Applied Biosystems, run on the ABI Prism 7700 Sequence Detection systems v 1.7 (Foster City, CA). The TS promoter repeat and promoter SNP polymorphisms and the 3’ untranslated region 6 bp deletion polymorphism were determined using published methods to detect PCR product size and RFLP-PCR assays respectively. Results: 22 pts were genotyped from 34 enrolled. There was no significant difference in characteristics between pts with and without genotype data. For the MTHFR polymorphism C677T, there was a trend towards decreased disease control rate (DCR) (CR/PR/SD) (p = 0.058, Jonckheere-Terpstra trend test) and worse TTP (p = 0.04) transitioning from variant CC to CT to TT; comparing TT genotype versus CT and CC combined, pts with TT had inferior DCR (p = 0.03) and TTP (p = 0.0003); homozygotes with TT had a median TTP of 2.6 months (mo) 95% CI (1.4, NA) versus 5.6 mo (4.2, 11.4) for pts with CT or CC variants. For the MTHFR A1298C SNP, there was no significant difference in DCR between variants, median TTP for homozygotes pts with AA was 4.1 mo (2.6, NA) vs. 6.7 mo (5.1, NA) in pts with AC or CC variants (p = 0.084); median overall survival for AA was 10.2 mo (7.6, NA) and for AC or CC 17.6 mo (17, NA) (p = 0.045). The MTHFR G1793A and TS polymorphisms did not impact DCR, TTP or overall survival. There was no association between any polymorphism and the incidence of grade >2 toxicities. Conclusions: Polymorphisms in MTHFR are potentially associated with antitumor efficacy of P-based therapy in recurrent or metastatic SCCHN. These results warrant validation in larger studies with P in SCCHN. No significant financial relationships to disclose.

Lack of carotid stiffening associated with MTHFR 677TT genotype in cardiorespiratory fit adults

2010 ◽  
Vol 42 (2) ◽  
pp. 259-265 ◽  
Author(s):  
Motoyuki Iemitsu ◽  
Haruka Murakami ◽  
Kiyoshi Sanada ◽  
Kenta Yamamoto ◽  
Hiroshi Kawano ◽  
...  
Keyword(s):  
Arterial Stiffness ◽  
Cardiorespiratory Fitness ◽  
Methylenetetrahydrofolate Reductase ◽  
Homocysteine Level ◽  
Mthfr C677t ◽  
Plasma Homocysteine ◽  
C677t Polymorphism ◽  
Significant Interaction Effect ◽  
Mthfr C677t Polymorphism ◽  
Fitness Level

The TT genotype of C677T polymorphism in 5,10-methylenetetrahydrofolate reductase (MTHFR) induces elevation of homocysteine level and leads to atherosclerosis and arterial stiffening. Furthermore, cardiorespiratory fitness level is also associated with arterial stiffness. In the present study, a cross-sectional investigation of 763 Japanese men and women (18–70 yr old) was performed to clarify the effects of cardiorespiratory fitness on the relationship between arterial stiffness and MTHFR C677T gene polymorphism. Arterial stiffness was assessed by carotid β-stiffness with ultrasonography and tonometry. The study subjects were divided into high-cardiorespiratory fitness (High-Fit) and low-cardiorespiratory fitness (Low-Fit) groups based on the median value of peak oxygen uptake in each sex and decade. The plasma homocysteine level was higher in the TT genotype of MTHFR C677T polymorphism compared with CC and CT genotype individuals. MTHFR C677T polymorphism showed no effect on carotid β-stiffness, but there was a significant interaction effect between fitness and MTHFR C677T polymorphism on carotid β-stiffness ( P = 0.0017). In the Low-Fit subjects, carotid β-stiffness was significantly higher in individuals with the TT genotype than the CC and CT genotypes. However, there were no such differences in High-Fit subjects. In addition, β-stiffness and plasma homocysteine levels were positively correlated in Low-Fit subjects with the TT genotype ( r = 0.71, P < 0.0001), but no such correlations were observed in High-Fit subjects. In CC and CT genotype individuals, there were also no such correlations in either fitness level. These results suggest that the higher cardiorespiratory fitness may attenuate central artery stiffening associated with MTHFR C677T polymorphism.

scholarly journals METHYLENETETRAHYDROFOLATE REDUCTASE C677T GENE POLYMORPHISM AND PROSTATE CANCER RISK

2018 ◽  
Vol 11 (5) ◽  
pp. 387
Author(s):  
Samah Tellouche-bouhouhou ◽  
Djalila Chellat-rezgoune ◽  
Noureddine Abadi ◽  
Dalila Satta ◽  
Abderrezak Dahdouh
Keyword(s):  
Prostate Cancer ◽  
Methylenetetrahydrofolate Reductase ◽  
Cancer Susceptibility ◽  
Prostate Cancer Risk ◽  
Mthfr C677t ◽  
Mthfr Gene ◽  
Single Nucleotide ◽  
Mthfr C677t Polymorphism ◽  
Increased Risk ◽  
Significant Difference

Objective: The single nucleotide polymorphism C677T of the methylenetetrahydrofolate reductase (MTHFR) gene encodes a thermolabile enzyme. This polymorphism was found to be implicated in cancer susceptibility. In this study, we analyzed the distribution of the MTHFR C677T polymorphism in two cohorts; patients and controls native of East of Algeria to explore the possible association between this polymorphism and prostate cancer susceptibility.Methods: Our examination has been conducted in 98 cases and 98 healthy controls. Genotyping was realized by polymerase chain reaction-restriction fragment length polymorphism method.Results: Compared with CC homozygous, the CT heterozygous was found to have a significantly increased risk of prostate cancer (p=0.04; odds ratio [OR]=2.01, 95% confidence interval [CI]: 1.02–3.95). However, no statistically significant difference was observed concerning the TT homozygous (p=0.74; OR=1.25, 95% CI: 0.51–3.04).Conclusion: Our results indicate that the genotype CT is a risk factor for prostate cancer in East of Algeria.

Homocysteine, folate, methylene tetrahydrofolate reductase genotype and vascular morbidity in diabetic subjects

2002 ◽  
Vol 102 (6) ◽  
pp. 631-637 ◽  
Author(s):  
Joey M. KAYE ◽  
Kim G. STANTON ◽  
Vincent J. MCCANN ◽  
Samuel D. VASIKARAN ◽  
Valerie BURKE ◽  
...  
Keyword(s):  
Vascular Disease ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr Gene ◽  
Plasma Homocysteine ◽  
Serum Folate ◽  
Type I ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Mthfr Genotype ◽  
Erythrocyte Folate

In the present study, the determinants of fasting plasma homocysteine in diabetic subjects were examined; whether plasma homocysteine and vascular disease are related and the influence of the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene on serum and erythrocyte folate, plasma homocysteine and vascular disease. Diabetic clinic subjects (Type I, n = 354; Type II, n = 392) were recalled for a cross-sectional survey. Standard methods were used to measure biochemical variables and to characterize vascular disease and MTHFR genotype. Plasma homocysteine was significantly and directly related to age, male sex and serum urea, and inversely related to serum folate and vitamin B12, independently in stepwise regression. When corrected for age and sex, homocysteine was significantly related to hard end points of coronary artery disease and stroke (each P<0.01), remaining significant when additionally adjusted for serum folate (P = 0.043 and P = 0.019 respectively). Serum folate was not clearly related to these events, although there was a trend to associate with the lower quintile of serum folate. The MTHFR genotype was not a determinant of plasma homocysteine, even in those in the lowest quintile of serum folate, nor of vascular disease. TT homozygosity at residue 677 was associated with elevation of total erythrocyte folate compared with both other genotypes (P<0.0001), almost certainly due to the diversion of 5,10-methylenetetrahydrofolate into derivates subsequent to the partial metabolic block that results from the MTHFR enzyme defect. In conclusion, in this clinic cohort of people with diabetes, vascular disease is related to plasma homocysteine, which is correlated with serum folate. The MTHFR genotype does not significantly influence either plasma homocysteine or vascular disease, despite it being a determinant of erythrocyte folate, which reflects its effect on folate metabolism.

scholarly journals Methylenetetrahydrofolate reductase gene polymorphism and its association with coronary artery disease

2007 ◽  
Vol 125 (1) ◽  
pp. 4-8 ◽  
Author(s):  
Alexandre Rodrigues Guerzoni ◽  
Érika Cristina Pavarino-Bertelli ◽  
Moacir Fernandes de Godoy ◽  
Carla Renata Graça ◽  
Patrícia Matos Biselli ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr C677t ◽  
Plasma Homocysteine ◽  
C677t Polymorphism ◽  
Specific Patient ◽  
Mthfr C677t Polymorphism ◽  
Artery Disease

CONTEXT AND OBJECTIVE: Obstructive coronary artery disease (CAD) is characterized by the deposition of atherosclerotic plaque on the coronary artery wall. Its manifestations depend on interactions between environmental and genetic risk factors. The aim of this work was to analyze the frequency of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in patients with CAD and its association with plasma homocysteine levels. Risk factors for CAD were also evaluated. DESIGN AND SETTING: Retrospective with blind quantitative analysis, at Hospital de Base, Faculdade de Medicina de São José do Rio Preto. METHODS: One hundred and twenty-seven individuals were studied. All completed a questionnaire to analyze risk factors for CAD. MTHFR polymorphism was investigated by restriction fragment length analysis and correlated with the number of affected arteries and degree of arterial obstruction determined by coronary cineangiography, and with plasma homocysteine levels measured by liquid chromatography/sequential mass spectrometry. RESULTS: Smoking (p = 0.02) and high-density lipoprotein cholesterol (p = 0.01) were associated with CAD. The C allele was the most prevalent in patients (0.61) and controls (0.66). There was no correlation between MTHFR/C677T polymorphism and plasma homocysteine levels. However, in patients with the TT genotype there was a correlation with the prevalence of coronary obstruction greater than 95% (p = 0.02) and the presence of two affected arteries (p = 0.04). CONCLUSIONS: The TT genotype is associated with coronary artery obstruction greater than 95% and the presence of two affected arteries. This confirms the relationship between genetic variants in specific patient subgroups and cardiovascular diseases.

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