title: Renal cell carcinoma does not express argininosuccinate synthetase and is highly sensitive to arginine deprivation via arginine deiminase.
abstract: Recently, pegylated arginine deiminase (ADI; EC 3.5.3.6) has been used to treat the patients with hepatocellular carcinoma or melanoma, in which the level of argininosuccinate synthetase (ASS) activity is low or undetectable. The efficacy of its antitumor activity largely depends on the level of intracellular ASS, which enables tumor cells to recycle citrulline to arginine. Thus, we examined the expression levels of ASS in various cancer cells and found that it is low in renal cell carcinoma (RCC) cells, rendering the cells highly sensitive to arginine deprivation by ADI treatment. Immunohistochemical analysis revealed that in biopsy specimens from RCC patients (n = 98), the expression of ASS is highly demonstrated in the epithelium of normal proximal tubule but not seen in tumor cells. Furthermore, RCC cells treated with ADI showed remarkable growth retardation in a dose dependent manner. ADI also exerted in vivo antiproliferative effect on the allografted renal cell carcinoma (RENCA) tumor cells and prolonged the survival of tumor-bearing mice. Histological examination of the tumors revealed that tumor angiogenesis and vascular endothelial growth factor (VEGF) expression were significantly diminished by ADI administration. Therefore, these findings suggest that arginine deprivation by ADI could provide a beneficial strategy for the treatment of RCC in ways of inhibitions of arginine availability and neovascularization.
authors.affiliation: Department of Urology, College of Medicine, Korea University, Seoul 136-705, Korea.
authors.forename: Cheol-Yong
authors.initials: CY
authors.lastname: Yoon
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Shim
authors.forename: Eun-Ho
authors.initials: EH
authors.lastname: Kim
authors.forename: Ju-Han
authors.initials: JH
authors.lastname: Lee
authors.forename: Nam-Hee
authors.initials: NH
authors.lastname: Won
authors.forename: Jeong-Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Park
authors.forename: Duck-Ki
authors.initials: DK
authors.lastname: Yoon
authors.forename: Bon-Hong
authors.initials: BH
authors.lastname: Min
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001119:Arginase / Q000737:chemistry / Q000494:pharmacology*; D001120:Arginine / Q000172:deficiency*; D001124:Argininosuccinate Synthase / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D002956:Citrulline / Q000378:metabolism; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000494:pharmacology; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D002956:Citrulline; D011092:Polyethylene Glycols; D001120:Arginine; D006867:Hydrolases; D001119:Arginase; C019723:arginine deiminase; D001124:Argininosuccinate Synthase