Chemistry Reference
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tubulin polymerization and/or microtubule stability (including those that may addi-
tionally affect drug binding). Thus, these mutations may not only affect drug-target
interactions, but they may also (or alternatively) impair intrinsic tubulin functions
in a way that could result in hypostable microtubules.
37,59
Consistent with this
hypothesis (previously formulated by Cabral and Barlow based on observations
made with paclitaxel-resistant CHO cells
61
), these cell lines are hypersensitive to
tubulin-depolymerizing drugs, such as vincristine or colchicine.
Epothilones retain significant activity against paclitaxel-selected cell lines that
harbor a distinct set of tubulin mutations,
22
and again this could perhaps translate
into clinical utility in the treatment of Taxol-resistant tumors. However, any such
predictions must be treated with great caution, as the clinical significance of indi-
vidual resistance mechanisms identified in vitro has not been established.
1.2.2
In Vivo Antitumor Activity
The in vivo effects of Epo B have been investigated in some detail by a group at the
Sloan-Kettering Cancer Center as well as by our group at Novartis. Initial experi-
ments by the Sloan-Kettering group in xenograft models of human leukemia
[CCRF-CEM and CCRF-CEM/VBL (MDR)] in CB-SCID mice (drug-sensitive
as well as multidrug-resistant tumors) suggested promising antitumor activity but
also a narrow therapeutic window.
62
In subsequent experiments, the compound
was found to exhibit considerable toxicity, while having only limited effects on
tumor growth in human MX-1 breast or SKOV-3 ovarian tumors in mice. These
data led to the conclusion that Epo B might simply be too toxic to become a clini-
cally useful anticancer agent.
63
In contrast to these findings, studies in our laboratory have demonstrated potent
antitumor activity of Epo B in several drug-sensitive human tumor models (nude
mice) upon intravenous administration, despite the compound's limited plasma sta-
bility in rodents.
20
Activity was observed for models encompassing all four major
types of solid human tumors (lung, breast, colon, and prostate) and was manifest
either as profound growth inhibition (stable disease) or significant tumor regression.
In addition, Epo B was found to be a potent inhibitor of tumor growth in P-gp-over-
expressing multidrug-resistant human tumor models. Regressions were observed
in two such models (KB-8511 (epidermoid carcinoma)
20
and HCT-15 (colon
carcinoma)
64
), where tumors were either poorly responsive or completely nonre-
sponsive to treatment with Taxol. In general, therapeutic effects could be achieved
at tolerated dose levels, but significant body weight loss was observed in several
experiments (which was generally reversible after cessation of treatment), which
indicates a relatively narrow therapeutic window. As demonstrated in a recent study
by Pietras et al., the antitumor effect of Epo B in a model of human anaplastic
thyroid carcinoma can be potentiated by coadministration with the tyrosine kinase
inhibitor STI571 (Gleevec) without any obvious decrease in tolerability.
65
The
enhanced antitumor activity of the combination is presumed to be a consequence
of a selective enhancement in drug uptake by the tumor because of inhibition of
platelet-derived growth factor receptor (PDGF-R) by STI571.
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