Reduction of difluoromethylornithine-induced thrombocytopenia in rats with ornithine while maintaining antitumor activity.
The purpose of this study was to evaluate the effect of a concomitant infusion of ornithine on the difluoromethylornithine (DFMO)-induced thrombocytopenia and antitumor activity. Male Fischer 344 rats with either a transplantable fibrosarcoma or Ward colon tumor were given a 12-day continuous infusion of DFMO (2000 mg/kg/day) alone or with ornithine. The dose of ornithine was defined as the molar ratio to DFMO. A continuous infusion of DFMO significantly reduced circulating platelet counts to 5-16% of the control. Concomitant ornithine treatment at a molar ratio of 0.2-0.5 resulted in protection of the rat from thrombocytopenia while the antiproliferative activity of DFMO against the fibrosarcoma or Ward colon tumor was unaffected. At a higher ornithine: DFMO molar ratio (0.7), the DFMO-induced inhibition of tumor growth was blocked. Tissue polyamine levels suggest a different sensitivity of tumor and normal tissue to DFMO. Concomitant ornithine resulted in a greater increase in the polyamine levels of normal tissues, compared with the tumor. These results suggest that ornithine can selectively inhibit DFMO-induced thrombocytopenia while not affecting the antitumor activity.
Grossie
V B
VB
Department of General Surgery, University of Texas M.D. Anderson Hospital and Tumor Institute, Houston 77030.
Ota
D M
DM
Ajani
J A
JA
Chang
T H
TH
Patenia
D
D
Nishioka
K
K
D000818:Animals; D015317:Biogenic Polyamines / Q000032:analysis; D000518:Eflornithine / Q000627:therapeutic use / Q000633:toxicity*; D008297:Male; D009952:Ornithine / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D012513:Sarcoma, Experimental / Q000188:drug therapy; D013921:Thrombocytopenia / Q000139:chemically induced / Q000517:prevention & control*
D015317:Biogenic Polyamines; D009952:Ornithine; D000518:Eflornithine