Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled trial.

Cascinu, Stefano; Cordella, L; Ferro, E Del; Fronzoni, M; Catalano, G.

doi:10.1200/jco.1995.13.1.26

Cited by 155 publications

(105 citation statements)

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“…clutathione and bone marrow support w-ith the haematopoietic growth factor filgrastim determined objectixe responses in 25 of 34 advanced gastric cancer patients Nx-ith a mild toxicitx (Cascinu et al 1993 Glutathione was gixen at a dose of 1.5 m-in 100 ml of normal saline ox er 15 min immediately before each CDDP administration to prevent CDDP-associated neurotoxicity as indicated by our previous experience (Cascinu et al 1995). Standard intraxvenous hydration was used: 2 h before initiation of the CDDP infusion.…”

Section: Epidoxorubicin (Epiadr) Cisplatin (Cddp)mentioning

confidence: 99%

Intensive weekly chemotherapy for locally advanced gastric cancer using 5-fluorouracil, cisplatin, epidoxorubicin, 6S-leucovorin, glutathione and filgrastim: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD)

Cascinu

Labianca²,

Graziano³

et al. 1998

Br J Cancer

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Summary Local extension prevents curative resection in more than two-thirds of gastric cancer patients. Unfortunately, resectability is one of the main prognostic factors in these patients, and survival is longer when tumours are completely removed. Preoperative chemotherapy is an attractive concept for obtaining curative resection. Thirty-two locally advanced unresectable gastric cancer patients were enrolled in five Italian Group for the Study of Digestive Tract Cancer (GISCAD) centres. For 16 patients, surgical unresectability was based on computerized tomography scan evaluation of tumour size (four patients) and invasion of adjacent structures (12 patients), whereas in another 16 patients locally advanced disease was confirmed by laparotomy. They received weekly administration of cisplatin 40 mg m-2. 5-fluorouracil 500 mg in-2, epidoxorbicin 35 mg m-2, 6S-stereoisomer of leucovorin 250 mg rT2 and glutathione 1.5 g m-2. From the day after to the day before each chemotherapy administration, filgrastim was administered by subcutaneous injection at a dose of 5 lig kg-'. One cycle of therapy consisted of eight weekty treatments. Fifteen of 32 patients (470o) responded to chemotherapy, whereas 13 (410%) had stable disease and four (12°h) progressed on therapy. Of the 15 responding patients, 13 were completely resected after chemotherapy and two of them had a complete pathological response. Two clinically responding patients were found unresectable at operation because of perntoneal seeding. At a median follow-up from the start of treatment of 24 months (range 11-39 months), 10 of 13 resected patients are alive and eight are relapse free. Three patients died after 11, 12. and 14 months respectively. Toxicity was acceptable: side-effects consisted mainly of grade 11 National Cancer Institute common toxicity criteria (NCICTC) leucopenia and thrombocytopenia in ten patients. Neither treatment-related death nor surgical complications in patients undergoing surgery were observed. This weekly intensive regimen enabled resection in half of previously inoperable tumours with a moderate toxicity. It can be offered to patients with locally advanced unresectable gastric cancer to obtain curative resection.

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Section: Epidoxorubicin (Epiadr) Cisplatin (Cddp)mentioning

confidence: 99%

Intensive weekly chemotherapy for locally advanced gastric cancer using 5-fluorouracil, cisplatin, epidoxorubicin, 6S-leucovorin, glutathione and filgrastim: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD)

Cascinu

Labianca²,

Graziano³

et al. 1998

Br J Cancer

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“…Witschi et al administered a single oral dose of up to 3 g of GSH to seven healthy subjects and did not observe an increase in blood GSH levels, concluding ''it is not feasible to increase circulating GSH to a clinically beneficial extent by the oral administration of 3 g of GSH.'' 22 Yet three studies have evaluated the impact of reduced GSH supplementation combined with oxidative chemotherapeutic agents in patients with various cancers [23][24][25] ; all three trials demonstrated reduced adverse effects of the chemotherapy without negative effects on the effectiveness of the regimen, suggesting some physiologic effect from oral dosing. Unfortunately GSH status was not measured in any of these trials.…”

Section: Introductionmentioning

confidence: 99%

Effects of Oral Glutathione Supplementation on Systemic Oxidative Stress Biomarkers in Human Volunteers

Allen

Bradley

2011

The Journal of Alternative and Complementary Medicine

133

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Background: The tripeptide glutathione (GSH) is the most abundant free radical scavenger synthesized endogenously in humans. Increasing mechanistic, clinical, and epidemiological evidence demonstrates that GSH status is significant in acute and chronic diseases. Despite ease of delivery, little controlled clinical research data exist evaluating the effects of oral GSH supplementation. Objectives: The study objectives were to determine the effect of oral GSH supplementation on biomarkers of systemic oxidative stress in human volunteers. Design: This was a randomized, double-blind, placebo-controlled clinical trial. Setting/location: The study was conducted at Bastyr University Research Institute, Kenmore, WA and the Bastyr Center for Natural Health, Seattle, WA. Subjects: Forty (40) adult volunteers without acute or chronic disease participated in this study. Intervention: Oral GSH supplementation (500 mg twice daily) was given to the volunteers for 4 weeks. Outcome measures: Primary outcome measures included change in creatinine-standardized, urinary F2-isoprostanes (F2-isoP) and urinary 8-hydroxy-2¢-deoxyguanosine (8-OHdG). Changes in erythrocyte GSH concentrations, including total reduced glutathione (GSH), oxidized glutathione (GSSG), and their ratio (GSH:GSSG) were also measured by tandem liquid chromatography/mass spectrometry. Analysis of variance was used to evaluate differences between groups. Results: There were no differences in oxidative stress biomarkers between treatment groups at baseline. Thirtynine (39) participants completed the study per protocol. Changes in creatinine standardized F2-isoP (ng/mg creatinine) (0.0 -0.1 versus 0.0 -0.1, p = 0.38) and 8-OHdG (lg/g creatinine) (-0.2 -3.3 versus 1.0 -3.2, p = 0.27) were nonsignificant between groups at week 4. Total reduced, oxidized, and ratio measures of GSH status were also unchanged. Conclusions: No significant changes were observed in biomarkers of oxidative stress, including glutathione status, in this clinical trial of oral glutathione supplementation in healthy adults.

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“…In particular, glutathione, N-acetylcysteine, and vitamin E (a-tocopherol) may have a clinical role in patient neuroprotection. 4,6,7,25,29,35 However, the major bias of these clinical trials resides in their small size and/ or in their short term follow-up. 2 An important limit in this field is the insufficient information on the molecular basis of the neuropathy.…”

mentioning

confidence: 99%

Oxaliplatin-Induced Neuropathy: Oxidative Stress as Pathological Mechanism. Protective Effect of Silibinin

Mannelli

Zanardelli

Failli

et al. 2012

The Journal of Pain

155

120

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Oxaliplatin is the standard treatment for advanced colorectal cancer. Its dose-limiting toxicity is the development of a painful neuropathic syndrome sustained by unclear mechanisms. Although the oxidative hypothesis is a matter of debate, direct data about oxidative damage induced in vivo by anticancer agents are lacking and the efficacy of the available antioxidant compounds are unsatisfactory. In a rat model of painful oxaliplatin-induced neuropathy (2.4 mgkg À1 i.p., daily for 21 days), we described an important component of oxidative stress. In the plasma of oxaliplatin-treated rats, the increases in carbonylated protein and thiobarbituric acid reactive substances were the index of the resultant protein oxidation and lipoperoxidation, respectively. The same pattern of oxidation was revealed also in the sciatic nerve, and in the spinal cord where the damage reached the DNA level. The antioxidant compound silibinin (100 mgkg À1 per os), administered once a day, starting from the first day of oxaliplatin injection until the 20th, prevented oxidative damage as did a-tocopherol. Repetitive administration of silibinin, as well as a-tocopherol, reduced oxaliplatin-dependent pain induced by mechanical and thermal stimuli. Antioxidants were also able to improve motor coordination. The antineuropathic effect of both molecules improved by about 50% oxaliplatin-induced behavioral alterations.Perspective: This study characterizes oxidative stress parameters in a rat model of oxaliplatininduced neuropathy. A relationship between the improvement of oxidative alterations and pain relief is established in rats treated with natural antioxidant compounds like a-tocopherol and silibinin. Silibinin could be a valid therapeutic option for chemotherapy-induced neuropathy.

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Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled trial.

Abstract: This study provides evidence that GSH is a promising and effective new drug for the prevention of CDDP-induced neuropathy, and that it does not reduce the clinical activity of chemotherapeutic drugs.

Cited by 155 publications

References 0 publications

Intensive weekly chemotherapy for locally advanced gastric cancer using 5-fluorouracil, cisplatin, epidoxorubicin, 6S-leucovorin, glutathione and filgrastim: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD)

Intensive weekly chemotherapy for locally advanced gastric cancer using 5-fluorouracil, cisplatin, epidoxorubicin, 6S-leucovorin, glutathione and filgrastim: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD)

Effects of Oral Glutathione Supplementation on Systemic Oxidative Stress Biomarkers in Human Volunteers

Oxaliplatin-Induced Neuropathy: Oxidative Stress as Pathological Mechanism. Protective Effect of Silibinin

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