Microbial flora in the gastrointestinal tract abolishes cytostatic effects of alpha-difluoromethylornithine in vivo.
Although treatment with the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO) leads to depletion of intracellular polyamines and to related growth inhibition in vitro, its cytostatic effects in vivo are disappointing. This may be due to abolition of DFMO-induced growth inhibition by polyamines released during normal body cell turnover, to dietary polyamines, or to putrescine synthesized by the microbial flora in the GI tract. We studied selectively (aerobic) and totally (aerobic + anaerobic) GI tract-decontaminated LI210-bearing mice fed with 3 types of diet differing in their polyamine and carbohydrate residue contents and treated with combinations of intraperitoneal DFMO and oral deuterium-labelled putrescine. Our data show that, irrespective of diet type, total decontamination markedly potentiates the moderate tumor growth inhibition that is caused by DFMO alone. During total decontamination, growth-inhibited L1210 cells accumulate in the G0/G1 phase of the cell cycle. Although orally administered deuterium-labelled putrescine gave rise to deuterium labelling of L1210 putrescine, spermidine and spermine, the polyamine levels in our diets played only a minor role.
Hessels
J
J
Central Laboratory for Clinical Chemistry, University Hospital Groningen, The Netherlands.
Kingma
A W
AW
Ferwerda
H
H
Keij
J
J
van den Berg
G A
GA
Muskiet
F A
FA
D000818:Animals; D015317:Biogenic Polyamines / Q000032:analysis / Q000378:metabolism; D003131:Combined Modality Therapy; D003903:Deuterium; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D004064:Digestive System / Q000382:microbiology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D000518:Eflornithine / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D005243:Feces / Q000032:analysis / Q000382:microbiology; D005260:Female; D007939:Leukemia L1210 / Q000178:diet therapy / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008811:Mice, Inbred DBA; D011700:Putrescine / Q000008:administration & dosage; D013047:Specific Pathogen-Free Organisms
D015317:Biogenic Polyamines; D004040:Dietary Carbohydrates; D003903:Deuterium; D011700:Putrescine; D000518:Eflornithine