Arginine deiminase as an Anti-Cancer Therapy

描述：肝细胞癌对精氨酸的特殊需求

DESCRIPTION: The distinctive arginine requirement of hepatocellular carcinomas and malignant melanomas provides the basis for a new potential chemotherapy. Just as acute lymphocytic leukemia cells require asparagine and E. coli asparaginase enzyme can be used to effect a cure for this disease, we propose using a mycoplasma derived arginine deiminase (ADI) to treat hepatocellular carcinoma and malignant melanomas. As a result of Phase I funding we have discovered a method where by ADI can be formulated with polyethylene glycol (PEG) such that it has a much longer circulating half-life in mice and is less immunogenic. When ADI formulated with PEG is injected into mice it selectively reduces the plasma levels of arginine and starves human melanomas and hepatocellular carcinomas implanted into these animals. This treatment is also being tested in dogs with spontaneous melanoma (under an INAD received from the FDA) and is quickly being proven to be an effective means of treating spontaneous melanoma with very few, if any, side effects. We have requested and received an Orphan Drug Designation for this project and in a Pre-IND meeting with the FDA and the Orphan drug Office, delineated the experiments needed to file a Phase I IND to permit human testing of this drug. The studies proposed in this grant reflect the FDA requirements and when completed will allow for the testing of ADI formulated with PEG in humans. The studies proposed include the validation of the process used to make (under GMP conditions) 3 lots of ADI-PEG, characterize these lots with validated procedures, obtain pharmacodynamic and pharmacokinetic data that will allow allometric modeling of the predicted human dosing and perform the necessary immunological and toxicological testing needed for this project to progress into human clinical testing. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE