Amelioration of thrombocytopenia with concomitant ornithine in sarcomabearing rats receiving high dose difluoromethylornithine

The dose limiting toxicity of difluoromethylornithine (DFMO), when administered by continuous infusion, is thrombocytopenia. DFMO-induced antitumor activity and thrombocytopenia were time- and dosedependent up to 1700 mg/kg/d when administered continuously for 12 days. Concomitant ornithine administration (at selected molar ratios to DFMO) ameliorated thrombocytopenia induced by DFMO at a dose of 2000 mg/kg/day without adversely affecting its antitumor activity. The purpose of this study was to determine if ornithine could ameliorate the thrombocytopenia of higher DFMO doses and increase the efficacy of DFMO. Fischer 344 male rats with a transplantable sarcoma in the right flank were given 2000 and 3500 mg/kg/d DFMO alone or with ornithine at a molar ratio of 0.4 for 8 days by continuous infusion. Concomitant ornithine infusion overcame the thrombocytopenia that was induced by either dose of DFMO without reducing the antitumor activity against the sarcoma. The antitumor activity, tumor polyamine levels, and tumor S-adenosylmethionine decarboxylase activity did not consistently change with increasing doses of DFMO or with the addition of ornithine to the infusion regimen. These results demonstrate that the thrombocytopenia induced by doses of DFMO greater than 2000 mg/kg/d can be ameliorated without compromising the antitumor activity.