Bizelesin (U-77779) is a highly potent bis-alkylating
antitumor agent that is effective against several
tumor systems in vitro and in vivo. V79 cells that were 125- to 250-fold resistant to
bizelesin developed after constant exposure to gradually increasing concentrations of the
drug. Resistant cells exhibited a multidrug-resistant phenotype and genotype as indicated by cross-resistant to several structurally and functionally unrelated drugs, e.g.,
colchicine,
actinomycin D, and
Adriamycin, and overexpression of mdr
mRNA. Very low levels of cross-resistance to the
alkylating agents cisplatin and
melphalan were seen. Multidrug-resistant mouse
leukemia (P388/
Adriamycin-resistant) and human (KB/
vinblastine-resistant) cells were also resistant to
bizelesin.
Bizelesin resistance was unstable and decreased when cells were grown in the absence of the
drug. Resistant and sensitive cell lines had similar levels of
glutathione, and
bizelesin cytotoxicity for resistant cells was not markedly affected by treatment with
buthionine sulfoximine. Cross-resistance between
bizelesin and several of its analogs is reported.