Login Register Cart 0
Generic placeholder image

Clinical Cancer Drugs

Editor-in-Chief

ISSN (Print): 2212-697X
ISSN (Online): 2212-6988

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe

Glutathione for Hepatotoxicity in Patients with Liver Cirrhosis and Advanced Hepatocellular Carcinoma Receiving Hepatic Arterial Infusion Chemotherapy

Author(s): Koichi Momiyama, Hidenari Nagai, Yu Ogino, Takanori Mukozu, Daigo Matsui, Teppei Matsui, Noritaka Wakui, Mie Shinohara, Yoshinori Igarashi and Yasukiyo Sumino

Volume 2, Issue 1, 2015

Page: [54 - 60] Pages: 7

DOI: 10.2174/2212697X02666150313003755

Price: $65

Abstract

Purpose: We have previously reported that hepatic arterial infusion chemotherapy (HAIC) prolongs the survival of patients with advanced hepatocellular carcinoma (aHCC). However, 5- fluorouracil (5-FU) has been found to exacerbate liver damage in patients with liver cirrhosis (LC). We also previously reported that HAIC might cause occult hepatotoxicity and induces fibrosis without elevation of aminotransferases. The aim of this study was to clarify the effect of glutathione (GSH) on the hepatotoxicity of HAIC in LC patients with aHCC. Methods: Forty-one adult Japanese patients with LC and aHCC underwent HAIC between 2004 and 2009 at our hospital, and achieved multiple partial responses or had stable disease. The patients were divided into two groups, which were a non-GSH group receiving HAIC alone (n = 21) and a GSH group treated with HAIC plus GSH (n = 20). HAIC was delivered via the proper hepatic artery every 5 days for 4 weeks. GSH (100 mg) was given by intravenous injection on each morning of HAIC. Results: The Child-Pugh (C-P) class was A for 12 patients from the non-GSH group and 9 patients from the GSH group, while it was B for 9 and 11 patients, respectively. In class A and B patients from the non-GSH group, the C-P score showed a significant increase after chemotherapy compared with before chemotherapy. In contrast, there was no significant change the C-P score after chemotherapy in the GSH group. There were also no significant changes in the serum markers of liver fibrosis after chemotherapy in the GSH group, although a significant increase was noted in the non-GSH group. Conclusions: In LC patients with aHCC receiving HAIC, GSH might inhibit hepatotoxicity related to occult fibrosis occurring elevation of aminotransferases.

Keywords: 5-FU, HCC, hepatic arterial infusion chemotherapy, hepatotoxicity, liver fibrosis, glutathione, 7S domain of type IV collagen, hyaluronic acid, N-terminal propeptide of type III procollagen.

Graphical Abstract

[1]
Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer 1985; 56: 918-28.
[2]
Nagasue N, Yukaya H, Hamada T, Hirosue S, Kanashima R, Inokuchi K. The natural history of hepatocellular carcinoma. A study of 100 untreated cases. Cancer 1984; 54: 1461-5.
[3]
Toyoda H, Nakano S, Kumada T, et al. The efficacy of continuous local arterial infusion of 5-fluorouracil and cisplatin through an implanted reservoir for severe advanced hepatocellular carcinoma. Oncology 1995; 52: 295-9.
[4]
Murata K, Shiraki K, Kawakita T, et al. Low-dose chemotherapy of cisplatin and 5-fluorouracil or doxorubicin via implanted fusion port for unresectable hepatocellular carcinoma. Anticancer Res 2003; 23: 1719-22.
[5]
Okuda K, Tanaka M, Shibata J, et al. Hepatic arterial infusion chemotherapy with continuous low dose administration of cisplatin and 5-fluorouracil for multiple recurrence of hepatocellular carcinoma after surgical treatment. Oncol Rep 1999; 6: 587-91.
[6]
Nagai H, Sumino Y. Therapeutic strategy of advanced hepatocellular carcinoma by using combined intra-arterial chemotherapy. Recent Patents Anticancer Drug Discov 2008; 3: 220-6.
[7]
Nagai H, Kanayama M, Higami K, et al. Twenty-four hour intraarterial infusion of 5-fluorouracil, cisplatin, and leucovorin is more effective than 6-hour infusion for advanced hepatocellular carcinoma. World J Gastroenterol 2007 14; 13(2): 280-284
[8]
Kanayama M, Nagai H, Sumino Y. Influence of the etiology of liver cirrhosis on the response to combined intra-arterial chemotherapy in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 2009; 64: 109-14.
[9]
Pinter M, Sieghart W, Graziadei I, et al. Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis. Oncologist 2009; 14: 70-6.
[10]
Suou T, Maruyama S, Nalamura H, et al. Increase in serum 7S domain of type IV collagen and N-terminal propeptide of type III procollagen levels with normal serum transaminase levels after long-term oral administration of Tegaful-Uracil. Hepatol Res 2002; 24: 184-91.
[11]
Nagai H, Matsui T, Kanayama M, et al. Hepatotoxicity of Intra-arterial combination chemotherapy in patients with liver cirrhosis and advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 2010; 66: 1123-9.
[12]
Yu JC, Jiang ZM, Li DM. Glutamine: a precursor of glutathione and its effect on liver. World J Gastroenterol 1999; 5: 143-6.
[13]
Friesen C, Kiess Y, Debatin KM. A critical role of glutathione in determining apoptosis sensitivity and resistance in leukemia cells. Cell Death Differ 2004; 11: S73-85.
[14]
Iwamiya T, Sawada S, Ohta Y. Repeated arterial infusion chemotherapy for inoperable hepatocellular carcinoma using an implantable drug delivery system. Cancer Chemother Pharmacol 1994; 33: S134-8.
[15]
Yamasaki T, Kurokawa F, Shirahashi H, et al. Novel arterial infusion chemotherapy using cisplatin, 5-fluorouracil, and leucovorin for patients with advanced hepatocellular carcinoma. Hepatol Res 2002; 23: 7-17.
[16]
Saitoh T, Satoh H, Nobuhara M, et al. Intravenous glutathione prevents renal oxidative stress after coronary angiography more effectively than oral N-acethylcysteine. Heart Vessels 2011; 26: 465-72.
[17]
Suou T, Yamada S, Hosho K, Yoshikawa N, Kawasaki H. Relationship between serum and hepatic 7S fragment of type IV collagen in chronic liver disease. Hepatology 1996; 23: 1154-8.
[18]
Suou T, Hosho K, Kishimoto Y, Horie Y, Kawasaki H. Long-term decrease in serum N-terminal propeptide of type III procollagen in patients with chronic hepatitis C treated with interferon alpha. Hepatology 1995; 22: 426-31.
[19]
Ueno T, Inuzuka S, Torimura T, et al. Serum hyaluronate reflects hepatic sinusoidal capillarization. Gastroenterology 1993; 105: 475-81.
[20]
Friedman SL. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. N Engl J Med 1993; 328: 1828-35.
[21]
Yamada S, Suou T, Kawasaki H, Yoshikawa N. Clinical significance of serum 7S collagen levels in various liver diseases. Clin Biochem 1992; 25: 467-70.
[22]
Yamada S, Kishimoto Y, Suou T, Kawasaki H, Horie Y. Heterogeneity of antigens related 7S domain of type IV collagen in serum: application to patients with chronic liver disease. Clin Chim Acta 1992; 212: 73-8.
[23]
Suou T, Yamada S, Hosho K, Yoshikawa N, Kawasaki H. Relationship between serum and hepatic 7S fragment of type IV collagen in chronic liver disease. Hepatology 1996; 23: 1154-8.
[24]
Teare JP, Sherman D, Greenfield SM, et al. Comparison of serum procollagen III peptide concentrations and PGA index for assessment of hepatic fibrosis. Lancet 1993; 342: 895-8.
[25]
Tengblad A, Laurent UB, Lilja K, et al. Concentration and relative molecular mass of hyaluronate in lymph and blood. Biochem J 1986; 236: 521-3.
[26]
Eriksson S, Fraser JRE, Laurent TC, Pertoft H, Smedstrod B. Endothelial cells are a site of uptake and degradation of hyaluronic acid in the liver. Exp Cell Res 1983; 144: 223-8.
[27]
Aruffo A, Stamenkovic I, Melnic M, Underhill CB, Steed B. CD44 is the principal cell surface receptor for hyaluronate. Cell 1990; 61: 1303-13.
[28]
Engstrom-Laurent A, Loof L, Nyberg A, Schroder T. Increased serum levels of hyaluronate in liver disease. Hepatology 1985; 5: 638-42.
[29]
Pares A, Deulofeu R, Gimenez A, et al. Serum hyaluronate reflects hepatic fibrogenesis in alcoholic liver disease and is useful as a marker of fibrosis. Hepatology 1996; 24: 1399-403.
[30]
Deneke SM, Fanburg BL. Regulation of cellular glutathione. Am J Physiol 1989; 257: L163-73.
[31]
Wada H, Nagano H, Yamamoto H, et al. Combination of interferon- alpha and 5-fluorouracil inhibits endothelial cell growth directly and by regulation of angiogenic factors released by tumor cells. BMC Cancer 2009 12; 9: 361.
[32]
Nakamura M, Nagano H, Sakon M, et al. Role of the Fas/FasL pathway in combination therapy with interferon-alpha and fluorouracil against hepatocellular carcinoma in vitro. J Hepatol 2007; 46: 77-88.

Rights & Permissions Print Cite
Article Metrics
27
4
© 2024 Bentham Science Publishers | Privacy Policy