Alleviation of intestinal lesions by combined treatment with a 5-fluoro-2'-deoxyuridine (FUDR) derivative and alpha-difluoromethylornithine (DFMO)[correction of DMFO] in tumor-bearing mice.
alpha-Difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, reduced intestinal lesions in tumor-bearing mice caused by treatment with N3-(3-methylbenzoyl)-3',5'-diacetyl [corrected]-FUDR (FF-705), a derivative of 5-fluoro-2'-deoxyuridine (FUDR). FF-705 at 32 mg/kg (the effective dose) suppressed tumor growth to about 40% of the control level. At this dose, body weight gain was suppressed slightly when FF-705 was given alone, and this change was milder in the DFMO-supplemented group. Intestinal lesions were suppressed almost completely by concomitant treatment with DFMO. The gross lesion index in the combined treatment group was similar to that in the controls and significantly smaller than in the FF-705-alone group (0.3 and 1.9, respectively). The histological lesion index in the combined treatment group was also significantly smaller than in the FF-705-alone group (7.9 and 23.8, respectively). When FF-705 was given at 64 mg/kg, the intestinal mucosal lesions were more severe, but DFMO supplementation reduced them by approximately 50%. Moreover, maltase and diamine oxidase activities of intestinal epithelium remained higher with combined treatment than with FF-705 alone. With FF-705 at 256 mg/kg (a toxic dose), DFMO had little protective effect against intestinal damage.
Takeshita
S
S
Development Laboratories, Hirakata Center, Marion Merrell Dow K.K., Osaka, Japan.
Nagatomi
H
H
Ando
K
K
D006631:Amine Oxidase (Copper-Containing) / Q000032:analysis; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001835:Body Weight; D000518:Eflornithine / Q000008:administration & dosage; D004906:Erythrocyte Count; D005467:Floxuridine / Q000008:administration & dosage / Q000031:analogs & derivatives; D007414:Intestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000473:pathology
D005467:Floxuridine; C040250:2'-deoxy-3',5'-di-O-acetyl-5-fluoro-3-(3-methylbenzoyl)uridine; D006631:Amine Oxidase (Copper-Containing); D000518:Eflornithine