posted on 2017-01-23, 15:18authored byApril
L. Risinger, Jing Li, Lin Du, Raymond Benavides, Andrew J. Robles, Robert H. Cichewicz, John G. Kuhn, Susan L. Mooberry
The taccalonolides are microtubule
stabilizers that covalently
bind tubulin and circumvent clinically relevant forms of resistance
to other drugs of this class. Efforts are under way to identify a
taccalonolide with optimal properties for clinical development. The
structurally similar taccalonolides AF and AJ have comparable microtubule-stabilizing
activities in vitro, but taccalonolide AF has excellent in vivo antitumor
efficacy when administered systemically, while taccalonolide AJ does
not elicit this activity even at maximum tolerated dose. The hypothesis
that pharmacokinetic differences underlie the differential efficacies
of taccalonolides AF and AJ was tested. The effects of serum on their
in vivo potency, metabolism by human liver microsomes and in vivo
pharmacokinetic properties were evaluated. Taccalonolides AF and AJ
were found to have elimination half-lives of 44 and 8.1 min, respectively.
Furthermore, taccalonolide AJ was found to have excellent and highly
persistent antitumor efficacy when administered directly to the tumor,
suggesting that the lack of antitumor efficacy seen with systemic
administration of AJ is likely due to its short half-life in vivo.
These results help define why some, but not all, taccalonolides inhibit
the growth of tumors at systemically tolerable doses and prompt studies
to further improve their pharmacokinetic profile and antitumor efficacy.