L-Ornithine Apartate – a Rationale for Its Use in Combination with Chemotherapy, Radiation, and Hyperthermia in Oncology

L-ornithine aspartate has been widely used in hepatology for its well-known effects on lowering blood ammonia concentrations by increasing urea synthesis (1). Moreover, accumulating evidence suggests that L-ornithine aspartate restores muscle protein synth- esis, an effect which can be exploited in patients suffering from cancer or HIV infections (2). Other studies showed significant improvements of clinical values and liver function in patients undergoing radiation therapy receiv- ing L-ornithine aspartate (3). Furthermore, L-ornithine aspartate increased the tolerance towards cytostatic drugs in patients receiv- ing chemotherapy (4). In this study with 157 patients the che- motherapy-induced increase in liver transaminases could be lim- ited, whereas the production of cholinesterase as parameter for li- ver function could be increased in patients receiving L-ornithine aspartate parallel to chemotherapy with antimetabolites, platinum derivatives, alkylating agents, anthrazyklines, and mitosis-inhibit- ing substances. Chemotherapy is known to induce transient states of hyperammonemia (5). The hypothesis is put forth that L-ornithine aspartate also may have a protective effect on proliferation kinetics of tumor cells. Re- cently, ammonium cholate has been shown to accelerate the growth of the MCF-7 cell line in vitro, an effect which may be blocked by the administration of L-ornithine aspartate (6). Ammo- nia has been shown to be associated with increased metastasis (7) as well as anorexia and showed a rise in activity, following the ad- ministration of intravenous injections of 13 N-labelled ammonia in different tumor types. Ammonia also is involved in the regulation of protein turnover in tumor cells. L-asparagine synthetase has been suggested as a marker for metastases. Moreover, in multiple myeloma growth has been allied with hyperammonemia (8). This hyperammonemia could be demonstrated not to be due to liver dysfunction but to increased production of ammonia by myeloma cells. Furthermore, progressive malignant growth in tumor-bearing animals correlated with increased ammoniagenesis and increased glutamine uptake in other tumor tissues and the liver (9). The hyperthermic treatment of cancer also induces high levels of ammonia in the tumor environment (10), indicating increased pro- teolysis reflected in the rise in urea. Taken together these findings indicate that conventional cancer treatments such as chemotherapy and radiation together with hy- perthermia are associated with a rise in the levels of ammonia both in the blood stream and the tumor microenvironment. On the other side, ammonia may function as a mediator for local tumor growth and metastasis. Hence, further experimental and clinical studies are indicated to investigate the potential of the administra- tion of L-ornithine aspartate as an adjunct to standard cancer treatment regimens.