Characterization of difluoromethylornithine-resistant mouse and human tumour cell lines.

Four mouse and two human tumour cell lines resistant to alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), were analysed for the activities of polyamine-biosynthetic and -biodegradative enzymes as well as for cellular polyamine contents. In all but one of these cell lines the resistance to DFMO was based on an overproduction of ODC. In a human myeloma cell line the resistance was based on a greatly enhanced arginase activity. Except for one L1210 variant cell line, all the resistant cell lines contained elevated S-adenosylmethionine decarboxylase activity. Similarly, all the resistant mouse, but not human, cell lines displayed enhanced spermidine and spermine synthase activities. Arginase activity was detected only in human cell lines. In both DFMO-resistant cell lines the activity of arginase was strikingly elevated. Of the biodegradative enzymes, polyamine oxidase activity was readily detectable in all mouse cells, but no measurable activity was found in the human cells. Spermidine/spermine N1-acetyltransferase activity was elevated in three out of four resistant mouse cell lines. Even though the concentration of spermidine was usually lower in the overproducer cells, this was compensated by an increased content of spermine. The two resistant human myeloma cells contained intracellular ornithine concentrations that were from more than 5 to more than 20 times higher than those in the parental cells.