The activity of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548), a new alkycycline with high antitumor activity against a broad range of
cancer cells, was evaluated in vitro and in vivo in cells selected for resistance to different
anticancer agents. Both in vitro and in vivo,
PNU-159548 did retain its activity in cells expressing the multidrug resistance (MDR) phenotype, associated to MIDR-1 gene overexpression or with an alteration in the
topoisomerase II gene (altered MDR), independently on the
drug used for the selection of the resistant cell line. According to these data, the intracellular uptake of
PNU-159548 is not influenced by the presence of MDR-1.
PNU-159548 was also active, both in vitro and in vivo, against cells showing resistance to various
alkylating agents iincluding
cisplatin,
cyclophosphamide, and
melphalan) and
topoisomerase I-inhibitors. Cells defective in nucleotide excision repair, which did show
hypersensitivity to treatment with UV irradiation and
alkylating agents, showed only a marginally increased sensitivity to
PNU-159548. Similarly, the activity of the
drug was not influenced by the mismatch repair system, as assessed in two different cellular systems deficient in hMLH1 expression and in which hMLH1 activity was restored by chromosome 3 transfer. The results obtained clearly indicate that the new
anticancer agent PNU-159548 is able to overcome the classical mechanisms of resistance emerging
after treatment with the most clinically used
anticancer agents, and it could represent an alternate choice in the treatment of those
tumors refractory to conventional
therapy.