Reduced tissue ornithine increases the cytotoxicity of difluoromethylornithine

Polyamines are low molecular weight cations that are essential for the growth of all cells. The polyamine inhibitor difluoromethylornithine (DFMO) will decrease tumor growth when administered parenterally; thrombocytopenia is the major dose-limiting toxicity. Since an essential amino acid-based total parenteral nutrition (TPN) regimen was shown to reduce the ornithine and polyamine content of a transplantable sarcoma in preliminary studies, the effect of the amino acid content of TPN on the antitumor activity of DFMO was evaluated.

Fischer 344 male rats were inoculated subcutaneously with a transplantable sarcoma and fed a restricted intake of Purina rodent chow-5001 (8 g/d, RI) for 12 days to induce malnutrition. Rats were then randomized to continue receiving the RI regimen or to receive one of two TPN regimens for an additional 6 days. Isocaloric TPN was formulated with essential amino acids (E) as the sole nitrogen source or with E and nonessential amino acids including arginine (ENA). DFMO (1000 mg/kg/d) was added to the infusate of one group of rats receiving each of the respective TPN regimens.

The growth rate of the sarcoma was significantly decreased (P < 0.05) when DFMO was administered with E for 6 days but not when given to rats receiving ENA. DFMO-related thrombocytopenia was greater when administered with E as compared with rats given ENA. The plasma and tissue levels of DFMO were not affected by the TPN amino acid content nor did DFMO have any effect on plasma or tissue ornithine levels. The plasma and tissue levels of ornithine, however, were significantly lower for rats given E as compared with rats receiving ENA or those continued on RI.

The results show that the cytotoxicity of DFMO was enhanced by an essential amino acid-based TPN. This increase was directly associated with a decrease in the plasma and tissue content of ornithine and polyamines.