Rhizoxin is an
antineoplastic drug that inhibits
tubulin polymerization. In this study, we demonstrated that
rhizoxin was approximately twice as active in vitro against a human
small-cell lung cancer cell line with non-
P-glycoprotein-mediated resistance to
vindesine, H69/VDS, as against its parental line, H69.
Tubulin polymerization in H69/VDS, demonstrated by Western blot analysis, was inhibited markedly by
rhizoxin compared with that in H69, in a concentration-dependent manner. A
drug-accumulation study showed that the intracellular
rhizoxin level in H69/VDS was 15% lower than that in H69, whereas efflux from H69/VDS was enhanced slightly. These results indicate that enhanced inhibition of
tubulin polymerization rather than increased intracellular
drug concentration accounted for the higher sensitivity of H69/VDS to
rhizoxin. In an experiment using mice with
severe combined immunodeficiency and inoculated subcutaneously with H69/VDS, in vivo
tumor growth was reduced markedly by three intermittent intraperitoneal doses of
rhizoxin compared with that in mice inoculated with H69. Three weeks after the last
rhizoxin dose, the relative treated/untreated
tumor volumes were 0.29 for H69, but only 0.06 for H69/VDS, indicating that H69/VDS regrowth was minimal even after a 3-week treatment-free period. In conclusion,
rhizoxin conquers
vindesine resistance of a human
small-cell lung cancer cell line in vitro and in vivo.