Biological activities of new anthracyclines containing fluorine, FAD104 and its metabolites.

From various new anthracyclines containing fluorine in their sugar moieties, 7-O-(2,6-dideoxy-2-fluoro-alpha-L-talopyranosyl)adriamycinone-14-hemi pimerate (FAD104) has been selected for clinical investigation, because of its excellent antitumor activity and solubility. In this paper, the mechanism whereby FAD104 exhibits good antitumor activity in vivo was studied through experiments in vitro in comparison with doxorubicin (DOX). FAD104 had weaker activity than DOX in DNA single and double strand scission in P388 cells and in binding to calf thymus DNA. FAD104 was taken up by P388 cells faster than DOX. The ester linkage in FAD104 was gradually hydrolyzed at neutral pH. FAD104 was metabolized to 7-O-(2,6-dideoxy-2-fluoro-alpha-L-talopyranosyl)adriamycinone (FT-ADM) when incubated with mouse or human serum. In mouse serum the esterase activity was about 100 times higher than in human serum. The product of nonenzymatic and enzymatic esterolysis, FT-ADM, was rapidly taken up by P388 cells and accumulated, reaching at a 9.7-fold higher level than DOX. Thus FAD104 was less active than DOX in itself, but it showed much higher activity through conversion into FT-ADM, due to the action of esterase or to spontaneous and gradual hydrolysis at physiological pH. 7-O-(2,6-Dideoxy-2-fluoro-alpha-L-talopyranosyl)adriamycinol (FT-ADM-OH), another metabolite found in mouse serum had the least biological activity among the fluorine-containing anthracycline glycosides, but its activity was still higher than DOX.