Cytostatic effects of α-difluoromethylornithine against experimental tumors in vivo:influence of gastrointestinal polyamines

Putrescine, spermidine and spermine contain two, three and four nitrogen atoms, respectively, interconnected by a carbon backbone. They are generally designated as polyamines. Under physiological conditions the nitrogen atoms are positively charged. Thus, in vivo polyamines behave as organic cations, that are known to bind with macromolecules, such as nucleic acids. By using specific inhibitors of their biosynthetic enzymes in cell cultures it became clear that polyamines are essential for the growth of both normal and tumor cells. Polyamine biosynthesis is therefore intensively studied as a possible target for cancer chemotherapy. Although polyamine biosynthesis is quite simple, the regulation of intracellular concentrations is complex. If polyamine levels are insufficient for cell proliferation several mechanisms may compensate for the imminent deficiency. Among these are upregulation of biosynthetic enzymes, downregulation of catabolic enzymes, and increase of polyamine transport from the extracellular compartment. The failure to induce a cytostatic effect in tumor bearing animals using a specific inhibitor of ornithine decarboxylase (the first enzyme in polyamine biosynthesis), stimulated us to investigate the in vivo uptake of polyamines from exogenous sources (notably the gastrointestinal tract)