Chain-fluorinated polyamines as tumor markers. II. Metabolic aspects in normal tissues.
The objective of this work was to study certain metabolic aspects of fluorine-substituted analogues of natural polyamines in healthy experimental animals, with the aim of exploring their potential application as tumor markers. Tissue polyamine concentrations were more effectively depleted by combined treatment with D,L-alpha-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, and N1,N4-bis-allenylputrescine, an inactivator of polyamine oxidase, than with either inhibitor alone. This suggests the general importance of polyamine interconversion as a metabolic source of putrescine. Administration of 2,2-difluoroputrescine after 2 weeks pretreatment with the two inhibitors caused the formation of 6,6-difluorospermidine and 6,6-difluorospermidine in nearly all tissues. Highest concentrations of the chain-fluorinated polyamines were observed in the small intestine. At 24 h after 2,2-difluoroputrescine administration the amount was about 8% of the normal endogenous polyamine pool in the small intestine, but lower in all other tissues. Replenishment of endogenous polyamine pools is a relatively slow process. Approximately 9 days after cessation of treatment with the two inhibitors normal values had been reestablished. The rate of formation of endogenous polyamines was not affected by the presence of their difluoro analogues. Elimination of the chain-fluorinated polyamines from tissues seems not to follow normal polyamine metabolic patterns. Their most rapid elimination coincides with the enhancement of endogenous polyamines, indicating that the fluoro analogues are displaced by the natural polyamines. Most of the 2,2-difluoroputrescine was rapidly excreted in the urine, and formation of a conjugate was detected. 6,6-Difluorospermidine was also a urinary excretion product. However, the metabolic fate of 6,6-difluorospermine could not be clarified. It was not found in urine, either free or as conjugate. The relatively low accumulation of chain-fluorinated polyamines, together with their rapid elimination from normal tissues are characteristics which together with their previously established selective uptake into rapidly proliferating tissues recommend them as potential tumor markers that can be determined by 19F-NMR spectroscopy.
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism*; D000518:Eflornithine / Q000494:pharmacology; D005461:Fluorine; D006207:Half-Life; D051379:Mice; D009955:Ornithine Decarboxylase / Q000032:analysis; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors; D011073:Polyamines / Q000032:analysis / Q000378:metabolism*; D011700:Putrescine / Q000031:analogs & derivatives / Q000494:pharmacology; D000097667:Polyamine Oxidase
D014408:Biomarkers, Tumor; D000518:Eflornithine; D005461:Fluorine; D009955:Ornithine Decarboxylase; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D011700:Putrescine; D000097667:Polyamine Oxidase; C044445:MDL 72527