Mechanisms of resistance to 6-aminonicotinamide

Several cell lines resistant to 6-aminonicotinamide (6-AN) have been isolated, some selected with 6-AN and others with tiazofurin. These cell lines have been characterized with respect to several parameters including cross-resistance to tiazofurin, ability to metabolize 6-AN or tiazofurin to the respective analog metabolites of NAD, accumulation of 6-phosphogluconate in the presence of drug, and levels of NAD pyrophosphorylase (EC 2.7.7.1). Cell lines selected with 6-AN (ANR) are not cross-resistant to tiazofurin and have retained the ability to synthesize the NAD analogs, 6-aminonicotinamide adenine dinucleotide (6-ANAD), the phosphorylated derivative (6-ANADP) and thiazole-4-carboxamide adenine dinucleotide (TAD) when treated with 6-AN or tiazofurin respectively. The cell lines selected with tiazofurin are all cross-resistant to 6-AN; the most resistant of the lines are unable to form the NAD analog metabolites in detectable amounts and appear deficient in NAD pyrophosphorylase (EC 2.7.7.1) activity, the enzyme that is presumably responsible for their formation. The parent CHO line accumulates 6-phosphogluconate in the presence of 6-AN indicating inhibition of 6-phosphogluconate dehydrogenase. Of the resistant cell lines only two of them accumulate this intermediate.