Association between the ERCC1 rs11615 polymorphism and clinical outcomes of oxaliplatin-based chemotherapies in gastrointestinal cancer: a meta-analysis.
Topic: Radiation/Chemotherapy

The relationship between the excision repair cross-complementing 1 (ERCC1) rs11615 polymorphism (C/T) and responses to oxaliplatin-based chemotherapy for gastric cancer (GC) and colorectal cancer (CRC) patients is controversial. Therefore, we performed a meta-analysis to assess this relationship.

PICO
Population: Patients with gastrointestinal cancer (GC and CRC) who have the ERCC1 rs11615 polymorphism (C/T)
Intervention: Oxaliplatin-based chemotherapy
Comparison: Non-carriers of the ERCC1 rs11615 polymorphism
Outcomes: Clinical outcomes of oxaliplatin-based chemotherapies in gastrointestinal cancer patients

Included studies:
title: Reactive arthritis--Giardia lamblia, another new pathogen?
title: Conjunctival transdifferentiation induced by systemic vitamin A deficiency in vascularized rabbit corneas.
abstract: Conjunctival transdifferentiation, the process in which conjunctival epithelium transforms into a cornea-like epithelium with the loss of goblet cells during the healing of a total corneal epithelial defect, can be retarded or reversed by corneal neovascularization. We have previously shown that this process normally occurring on non-vascularized corneas can be retarded or reversed by topical retinoids, suggesting that vitamin A may be one of the factors from blood circulation which is responsible for modulating transdifferentiation. Herein, we have examined the effect of systemic vitamin A deficiency on vascularized corneas starting 4 months after epithelial denudation, and compared this deficient group with their vascularized and non-vascularized controls. Mean serum retinol level (microgram/dl) (n = 4) measured by HPLC was gradually reduced from 83 of the controls to 20 in a 10 month follow-up. Topographical analysis disclosed a centrifugal loss of goblet cell density with time. Histology showed complete transdifferentiation in vascularized areas at 9 months, initiated by the loss of mucin contents from receding zones first noted at 2 months. Using impression cytology, all corneas were not keratinized and all conjunctivas maintained a normal goblet cell density at 10 months. These results indicate that conjunctival epithelium on corneal surface is more sensitive to the decrease of serum vitamin A levels than that on conjunctiva, and support the hypothesis that the relative vitamin A deficiency on vascularized corneas can also result in the conjunctival transdifferentiation.
title: Vitamin E for prevention of oxaliplatin-induced peripheral neuropathy: a pilot randomized clinical trial.
abstract: CONTEXT AND OBJECTIVE Oxaliplatin is one of the chemotherapy regimens most used for treating colorectal cancer. One of the main limitations to its use is induction of peripheral neuropathy. Previous studies have shown that vitamin E can reduce the incidence of peripheral neuropathy by 50%. This study aimed to assess the effectiveness of vitamin E for prevention of oxaliplatin-induced peripheral neuropathy. DESIGN AND SETTING Prospective, phase II, randomized pilot study developed at a university hospital in the Greater ABC region. METHODS Patients were randomized five days before starting oxaliplatin treatment, to receive either vitamin E or placebo until the end of the chemotherapy regimen. The outcome was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), version 3, and specific gradation scales for oxaliplatin-induced peripheral neuropathy. Patients with colorectal and gastric cancer who had been scheduled to receive oxaliplatin-based chemotherapy were included. Both groups received calcium and magnesium supplementation before and after oxaliplatin infusions. RESULTS Eighteen patients were randomized to the vitamin E group and 16 to the placebo group. Cumulative incidence of 83% with peripheral neuropathy grades 1/2 was observed in the vitamin E group, versus 68% in the placebo group (P = 0.45). A trend towards more diarrhea was observed among patients who received vitamin E (55.6% vs. 18.8%; P = 0.06). There were no other significant differences in toxicity between the groups. CONCLUSIONS No significant decrease in the incidence of acute oxaliplatin-induced peripheral neuropathy was demonstrated through vitamin E use.
title: Effects of proglumide on ductal and basolateral secretion of pancreatic digestive enzymes.
abstract: Previous studies have shown that proglumide acts as a cholecystokinin (CCK) receptor antagonist in isolated pancreatic acini. To establish the effect of proglumide in the intact organ, its effects on both CCK-stimulated ductal and basolateral secretion of digestive enzymes were studied in the in vitro rabbit pancreas. CCK-stimulated ductal secretion of chymotrypsinogen, amylase, and total protein, as well as basolateral secretion of amylase, was inhibited by proglumide in a dose-dependent manner. Regression lines comparing ductal chymotrypsinogen and amylase outputs also were altered significantly by proglumide in a dose-dependent manner, with amylase secretion inhibited to a lesser degree. Similarly, the relative rates of amylase secretion across the ductal versus the basolateral cell surface were altered, with basolateral secretion inhibited to a lesser degree. The effects seen with increasing concentrations of proglumide at a given concentration of CCK mirrored the effects seen with decreasing the concentration of CCK in the absence of proglumide. Proglumide did not affect ductal or basolateral secretion stimulated by a cholinergic agonist and did not affect unstimulated pancreatic secretion. Thus, proglumide appears to act as a selective antagonist of CCK-stimulated secretion in the intact organ. The results further indicate that interactions of an agonist and an antagonist at the CCK receptor can alter not only the overall amount of enzymes secreted but their relative proportions as well.
title: The primary structure of porcine Cu-Zn superoxide dismutase. Evidence for allotypes of superoxide dismutase in pigs.
abstract: Cu-Zn superoxide dismutase was purified to homogeneity from mixed pig blood and from a single pig. The isolated product had an absorption ratio 280/260 nm of 0.91, a specific activity of 3 000 +/- 200 units (cytochrome c reduction test), and an isoelectric point of 7.5 (chromatofocusing) or 7.25 (isoelectric focusing), respectively. Sequence determination was performed by automated solid-phase Edman degradation of fragments of the reduced S-carboxymethylated proteins obtained by digestion with trypsin or Staphylococcus aureus proteinase V8 or treatment with cyanogen bromide. Acetylation of the N-terminus was confirmed by comparing high performance liquid chromatography retention times of N-terminal peptides with those of authentic samples. Sequencing of the superoxide dismutase of mixed porcine blood revealed heterogeneity (70% Leu; 30% Val at position 29), whereas the sample derived from a single French pig proved to be homogeneous (100% Leu at position 29). The complete sequence of pig superoxide dismutase comprised 152 amino-acid residues, which corresponds to a theoretical molecular mass of 15 800 Da per subunit, and exhibited the expected high homology with those of other mammals. The aspartate and all 7 histidine residues known to complex the metal ions in bovine superoxide dismutase are conserved in the porcine sequence at the homologous positions Asp82 and His45, His47, His62, His70, His79, His119, respectively.
title: Variable response of serum magnesium and total cholesterol to different magnesium intakes and exercise levels in rats.
abstract: Thirty-two Sprague-Dawley rats were divided into four groups: control, exercise, low-magnesium diet, and a combination of low-magnesium diet and exercise. The low-magnesium diet contained 80 ppm of magnesium and the exercise consisted of 1-hour swim sessions, 5 days per week for 4 weeks. Serum magnesium was depressed and total cholesterol was elevated (p less than 0.05) in the low-magnesium diet, sedentary animals as compared to both sedentary and exercised rats fed a normal magnesium diet. The group on the combination of hypomagnesemic diet and exercise was not statistically different from the normal-diet group. It is concluded that exercise favorably affects the serum magnesium and cholesterol responses induced by a hypomagnesemic diet. There may be a threshold serum magnesium level to elicit the elevated cholesterol response, or other metabolic factors affected by exercise may modify the expected cholesterol response associated with deprivation or severe deficiency of dietary magnesium and related serum magnesium levels.
title: Polymorphisms in p53, GSTP1 and XRCC1 predict relapse and survival of gastric cancer patients treated with oxaliplatin-based adjuvant chemotherapy.
abstract: The aim of this study was to assess whether genetic polymorphisms in p53, glutathione S-transferase P1 (GSTP1), GSTM1, excision repair cross complementing group 1 (ERCC1) and X-ray repair cross-complementing group 1 (XRCC1) genes are associated with clinical outcome of gastric cancer patients treated with oxaliplatin-based adjuvant chemotherapy.
title: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and FOLFOX response in colorectal cancer patients.
abstract: * Numerous clinical studies, including a few prospective ones, have reported conflicting results on the impact of gene polymorphisms related to fluorouracil (FU) and oxaliplatin pharmacodynamics.
title: Pharmacogenetic approach for capecitabine or 5-fluorouracil selection to be combined with oxaliplatin as first-line chemotherapy in advanced colorectal cancer.
abstract: We studied the role of TS (5'VNTR, 5'SNP and 3'UTR), XRCC1-399, XPD-751, ERCC1-118 and XRCC3-241 genetic polymorphisms in tailoring fluroropyrimidine/oxaliplatin treatment. For this purpose, 110 XELOX (capecitabine/oxaliplatin)- or FUOX (fluorouracil/oxaliplatin)-treated metastatic colorectal cancer patients were selected prospectively for genotyping. In the FUOX group, TS-3'UTR +6bp/+6bp (hazards ratio, HR=2.62, p=0.007) and ERCC1-118C/T or C/C (HR=1.96, p=0.050) genotypes correlated with a shorter progression-free survival (PFS). When analysed jointly, the higher the number of favourable genotypes (FG) the longer the PFS (6.8m, 9.6m and 25.8m for 0, 1 or 2 FG; p=0.005). Disease-control rate was 100% in patients with 2 FG (87% and 38.5% for 1 or 0 FG; p=0.001). In the multivariate analysis, ERCC1-118 (HR=2.12, p=0.0037) and TS-3'UTR (HR=2.68, p=0.006) were strong independent prognostic factors. According to this, patients harbouring TS-3'UTR +6bp/+6bp and ERCC1-118C/T or C/C genotypes may better receive capecitabine instead of 5FU in an oxaliplatin-based first-line treatment.
title: Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy.
abstract: The objective is to investigate whether polymorphisms with putative influence on fluorouracil/oxaliplatin activity are associated with clinical outcomes of patients with advanced colorectal cancer treated with first-line oxaliplatin, folinic acid, and fluorouracil palliative chemotherapy.