Integrity and stability of the citrulline–arginine pathway in normal and tumour cell lines

Arginine catabolizing enzymes have been used on cancers for over 60 years. In the last 5 years the ability of arginine catabolizing enzymes, not only to inhibit proliferation, but to kill tumour cells has been reinvestigated. Selectivity of action lies in the inability of many tumours to circumvent arginine deprivation by recycling precursors through the urea cycle. While this offers an immediate window of opportunity to treat, e.g. melanomas and hepatocellular carcinomas (HCC) that have poor citrulline converting ability, it is possible that the deprivation can be applied to many other types of cancer. The problem of deficiency of the urea cycle enzymes in a wider range of normal and malignant cell lines has been addressed, and shown to be variable throughout several different tumour types. We also need to know how fickle recycling enzyme activity can be in both normal and tumour cells, and found to be remarkable stable. Increasing interest is shown in the amino acid (arginine) deprivation protocol because it has already moved into the clinic. Initial findings on a named-patient basis have been encouraging, and the development of a new rational approach to the systemic treatment of melanomas, HCCs and leukemias seems imminent. This is the more attractive because arginine deprivation protocols can also ‘stage’ tumour cells for combination therapy in cases where they might not be killed outright by deprivation alone.