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Molecular analysis of Fanconi anemia and mismatch repair genes in patients with colorectal carcinoma

Colombino, Maria and Avallone, Antonio and Izzo, Francesco and Tatangelo, Fabiana and Budroni, Mario and Cossu, Antonio and Galimi, Francesco and Comella, Pasquale and Botti, Gerardo and Sini, Maria Cristina and Tanda, Francesco and Palmieri, Giuseppe (2011) Molecular analysis of Fanconi anemia and mismatch repair genes in patients with colorectal carcinoma. Oncology Reports, Vol. 25 (4), p. 899-904. eISSN 1791-2431. Article.

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DOI: 10.3892/or.2011.1169

Abstract

Arginine deiminase (ADI), an arginine-degrading enzyme, has been used in the treatment of tumours sensitive to arginine deprivation, such as malignant melanoma (MM) and hepatocellular carcinoma (HCC). Endogenous production of arginine is mainly dependent on activity of ornithine transcarbamylase (OTC) and argininosuccinate synthetase (ASS) enzymes. We evaluated the effect of ADI treatment on OTC and ASS expression in a series of melanoma cell lines. Twenty-five primary melanoma cell lines and normal fibroblasts as controls underwent cell proliferation assays and Western blot analyses in the presence or absence of AIR Tissue sections from primary MMs (N=20) and HCCs (N=20) were investigated by immunohistochemistry for ASS expression. Overall, 21/25 (84%) MM cell lines presented a cell growth inhibition by ADI treatment; none of them presented constitutive detectable levels of the ASS protein. However, 7/21 (33%) ADI-sensitive melanoma cell lines presented markedly increased expression levels of the ASS protein following ADI treatment, with a significantly higher IC50 median value. Growth was not inhibited and the 1050 was not reached among the remaining 4/25 (16%) MM cell lines; all of them showed constitutive ASS expression. The OTC protein was found expressed in all melanoma cell lines before and after the ADI treatment. Lack of ASS immunostaining was observed in all analyzed in vivo specimens. Our findings suggest that response to ADI treatment in melanoma is significantly correlated with the ability of cells to express ASS either constitutively at basal level (inducing drug resistance) or after the treatment (reducing sensitivity to ADI).

Item Type:Article
ID Code:6241
Status:Published
Refereed:Yes
Uncontrolled Keywords:Colorectal tumorigenesis, DNA repair, immunohistochemistry, mutation analysis
Subjects:Area 05 - Scienze biologiche > BIO/17 Istologia
Area 05 - Scienze biologiche > BIO/13 Biologia applicata
Area 06 - Scienze mediche > MED/08 Anatomia patologica
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
001 Università di Sassari > 03 Istituti > Anatomia patologica
002 Altri enti e centri di ricerca del Nord Sardegna > CNR-Consiglio Nazionale delle Ricerche > Istituto di chimica biomolecolare, Sassari
Publisher:Spandidos Publications
eISSN:1791-2431
Deposited On:25 Jul 2011 11:30

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