Renal cell carcinoma does not express argininosuccinate synthetase and is highly sensitive to arginine deprivation via arginine deiminase.
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.
Yoon
Cheol-Yong
CY
Department of Urology, College of Medicine, Korea University, Seoul 136-705, Korea.
Shim
Young-Jun
YJ
Kim
Eun-Ho
EH
Lee
Ju-Han
JH
Won
Nam-Hee
NH
Kim
Jeong-Hun
JH
Park
In-Sun
IS
Yoon
Duck-Ki
DK
Min
Bon-Hong
BH
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
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