Drs. Brian J. Dillon, C. Mark Ensor, Frederick W. Holtsberg, John A. Bomalaski, and Mike A. Clark have a financial interest in ADI-PEG 20.
Incidence and distribution of argininosuccinate synthetase deficiency in human cancers
A method for identifying cancers sensitive to arginine deprivation
Article first published online: 16 JAN 2004
Copyright © 2004 American Cancer Society
Volume 100, Issue 4, pages 826–833, 15 February 2004
How to Cite
Dillon, B. J., Prieto, V. G., Curley, S. A., Ensor, C. M., Holtsberg, F. W., Bomalaski, J. S. and Clark, M. A. (2004), Incidence and distribution of argininosuccinate synthetase deficiency in human cancers. Cancer, 100: 826–833. doi: 10.1002/cncr.20057
- Issue published online: 3 FEB 2004
- Article first published online: 16 JAN 2004
- Manuscript Accepted: 25 NOV 2003
- Manuscript Revised: 14 NOV 2003
- Manuscript Received: 4 FEB 2003
- National Institutes of Health. Grant Numbers: 1R43-CA78028-01A1, 1R43-CA85023-01A2, 2R44-CA78028-02A1
- Food and Drug Administration. Grant Number: FDR 002 003-01
- argininosuccinate synthetase (ASS);
- arginine deiminase;
Argininosuccinate synthetase (ASS) was the first of two enzymes to convert citrulline to arginine. This pathway allowed cells to synthesize arginine from citrulline, making this amino acid nonessential for the growth of most mammalian cells. Previous studies demonstrated that several human tumor cell lines were auxotrophic for arginine due to an inability to express ASS. Selective elimination of arginine from the circulation of animals with these tumors is a potentially effective anticancer treatment. The purpose of these experiments was to determine the frequency of ASS deficiency and arginine auxotrophy in a variety of human malignant tumors.
The authors analyzed the expression of ASS by immunohistochemistry with a monoclonal antibody in a variety of human tumor biopsies. They found that the incidence of ASS deficiency varied greatly with the tumor type and tissue of origin.
Melanoma, hepatocellular carcinoma, and prostate carcinoma were most frequently deficient in ASS. Some human cancers were almost always positive for ASS (e.g., lung and colon carcinomas). However, other human cancers, including sarcomas, invasive breast carcinoma, and renal cell carcinoma, also were sometimes ASS deficient.
These data indicated that immunohistochemical detection of ASS may prove an effective means for determining ASS deficiency in malignant human tumors and for identifying patients most likely to respond to arginine deprivation therapy. Based on these results, human clinical trials using arginine-degrading enzyme therapy to treat patients with advanced melanoma or hepatocellular carcinoma have been initiated. Cancer 2004;100:826–33. © 2004 American Cancer Society.