Effect of ornithine in parenteral nutrition regimens on difluoromethylornithine-induced platelet suppression and changes in tumor polyamine content.
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 x 10(3)/mm3) or ENO (908 +/- 67 x 10(3)/mm3) were equivalent to those of chow fed rats (901 +/- 42 x 10(3)/mm3). ENA/DFMO rats had significant thrombocytopenia (607 +/- 185 x 10(3)/mm3), which was completely ameliorated for ENO/DFMO rats (939 +/- 111 x 10(3)/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.
Grossie
V B
VB
Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Nishioka
K
K
D000818:Animals; D001120:Arginine / Q000378:metabolism; D000518:Eflornithine / Q000494:pharmacology*; D006400:Hematocrit; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D009374:Neoplasms, Experimental / Q000378:metabolism; D009952:Ornithine / Q000008:administration & dosage*; D010288:Parenteral Nutrition; D010976:Platelet Count / Q000187:drug effects*; D011073:Polyamines / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
D011073:Polyamines; D001120:Arginine; D009952:Ornithine; D000518:Eflornithine