Red blood cell polyamine levels and host toxicity during continuous alpha-difluoromethylornithine infusion

The dose effects of continuous alpha-difluoromethylornithine (DFMO) infusion on red blood cell (RBC) polyamine levels, host toxicity and tumor growth were determined. Male rats with and without a transplantable methylcholanthrene-induced sarcoma received intravenously either 0.45% NaCl or DFMO at 500 mg, 1,000 mg, or 2,000 mg/kg body wt/day for 6 or 12 days. Dose-related inhibition of tumor growth was noted after the 12-day treatment. There were no changes in host carcass weight, food intake, plasma albumin, hematocrit or white blood cell counts. Platelet suppression was associated with the 1,000- and 2,000-mg doses with the 12-day treatment. Morphometry of the small intestine revealed mild but significant shortening of villi in the duodenum and jejunum at the 2,000-mg dose, but none of the animals developed diarrhea. The 500-mg DFMO dose reduced the rate of tumor growth without inducing platelet suppression or altering intestinal morphology. A decrease in RBC putrescine levels was noted at all doses. RBC spermidine levels increased with the 500-mg dose. RBC spermine levels were higher at all doses compared with controls. These results suggest that thrombocytopenia is the major dose-limiting side-effect of continuous DFMO infusion but does not occur at a dose of 500 mg/kg body wt/day.