Effect of Ornithine in Parenteral Nutrition Regimens on Difluoromethylornithine-Induced Platelet Suppression and Changes in Tumor Polyamine Content

Abstract

We have demonstrated that DFMO-induced thrombocytopenia can be ameliorated with concomitant ornithine (Orn) in chow-fed rats; a reversal in DFMO-associated tumor polyamine reduction and antitumor activity, however, was also evident. To determine the effect of Orn in total parenteral nutrition (TPN) regimens on DFMO-induced thrombocytopenia and changes in tumor polyamine concentrations, Ward-colon-tumor-bearing (WCT) rats were given TPN with arginine (ENA) or with ornithine substituted for arginine (ENO) alone or with DFMO (1.5 g/day) added directly to the infusate. After 4 days, the peripheral blood platelet counts for ENA (917 ± 151 × 10³/mm³) or ENO (908 ±67x 10³/mm³) were equivalent to those of chow-fed rats (901 ±42 × 10³/mm³). ENA/DFMO rats had significant thrombocytopenia (607 ± 185 × 10³/mm³), which was completely ameliorated for ENO/DFMO rats (939 ± 111 × 10³/mm³). Peripheral white blood count, hematocrit, and other hematological parameters were not affected. Tumor putrescine content for ENA rats (46.9 ±8.7 nmol/g) was equal to that for chow-fed rats (44.8 ± 6.2 nmol/g) and ENO rats (53.6± 8.3 nmol/g). The reduction in tumor putrescine content for ENO/DFMO rats (19.6 ±6.9 nmol/g) was equivalent to that of ENA/DFMO rats (14.7 ± 3.0 nmol/g). Tumor spermidine was reduced only for the ENA/DFMO rats while spermine was slightly elevated. Tumor spermine content for ENO/DFMO rats (57.2 ±12.0 nmol/g) was equal to that for ENO rats (65.6 ±8.7 nmol/g) but was significantly (p = 0.004)reduced when compared with rats receiving ENA/DFMO (89.4 ± 20.4 nmol/g). The results of this study show that TPN with Orn substituted for arginine can be used with a chemotherapeutic dose of DFMO to ameliorate the thrombocytopenia. The DFMO-induced reduction in tumor putrescine content, however, was not affected when Orn was substituted for arginine in a parenteral nutrition regimen. These results suggest that the antitumor activity of DFMO would not be adversely affected by coadministering DFMO with a TPN regimen with Orn substituted for arginine.