Research Project
6018217
The distinctive arginine requirement of hepatocellular carcinomas, malignant melanomas and some sarcomas provides the basis for a new potential chemotherapy. The enzyme arginine deiminase (ADI) can deplete serum arginine; moreover, the duration of this depletion is significantly extended by covalent attachment of polyethylene glycol (PEG) to ADI. Preliminary studies indicate that PEG-ADI treatment increases the survival of mice bearing sarcomas, hepatomas or melanomas. The anti-tumor efficacy of PEG-ADI was enhanced when a larger PEG was linked to ADI. Thus, the goals of this proposal are to identify highly efficacious PEG modifications of ADI, and thereby provide a foundation for the development of a PEG-ADI therapy in the treatment of malignant melanomas and hepatocellular carcinomas. In order to identify such optimal ADI modifications, linear PEGs, from 5 to 100 kDa, and branched PEGs will be coupled to ADI and the specific activities of the PEG-ADIs will be determined. The in vivo effectiveness of the PEG-ADIs, in depleting serum arginine, reducing ADI immunogenicity and increasing the survival of sarcoma bearing mice will be assessed. Then the anti-tumor efficacy of the three most promising PEG-ADIs will be evaluated in mice bearing human hepatomas and melanomas. PROPOSED COMMERCIAL APPLICATIONS: The proposed studies could lead to the development of a safe and effective therapy to combat malignant melanoma (stage 3) and hepatocellular carcinoma. Effective treatments for these neoplasias are currently not available and are urgently needed. In addition, there may be subsets of other neoplasias, which exhibit an arginine dependence, and hence might be candidates for PEG-ADI treatment.
