174
Cancer Chemotherapy, Theoretical Foundations of
specifc mechanisms in tumor cells, in
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drugs with increased specifcity For cancer.
Here, we review progress and provide a
snapshot oF this rapidly advancing feld.
Selected examples oF mechanism-based
drug design programs, which illustrate the
guiding principles behind the new era oF
cancer drug development, are discussed.
The success stories are clear; a situation
we anticipate will be repeated in the con-
tinuing eFForts to deliver tailored therapies
into the cancer clinic.
3
Gleevec and CML
Gleevec (ST1571) provides a paradigm
For a successFully developed, rationally
designed, and mechanism-based therapy
For the treatment oF a specifc cancer.
In chronic myelogenous leukemia (CML),
the consistent chromosomal abnormality,
the Philadelphia (Ph) chromosome, is a
translocation event between chromosome
9 and 22 that results in the bcr-
abl
Fusion
product derived From the juxtaposition oF c-
abl
oncogene and breakpoint cluster region
(bcr). bcr-
abl
is present in over 95% oF
CML patients and in about 5% oF acute
lymphoblastic leukemia (ALL) patients in
whom it Functions as a constitutively active
tyrosine kinase that is essential For the
oncogenic activity oF the Fusion protein
(±ig. 1).
Originally, Gleevec was identifed by
high-throughput screening For compounds
with kinase inhibitory activity, and was
subsequently
optimized
using
rational
drug design procedures For activity against
Abl tyrosine kinase in CML cells. A suc-
cessFul Phase I study indicated remarkable
single agent activity during CML blast cri-
sis (and Ph-positive ALL), although the
responses did not appear to be long
term. Nevertheless, the success in Phase I
prompted Further Phase II clinical analy-
sis, Followed by ±DA approval.
The appearance oF resistance to Gleevec
was a surprising clinical outcome: the
majority oF CML patients that relapse aFter
initial response have reactivated bcr-
abl
ki-
nase. Molecular analysis indicated that in
many cases resistant cells carry point mu-
tations in the
abl
kinase gene that rendered
the kinase less sensitive to STI571, For ex-
ample, at a site that would be predicted to
contact STI571 From the crystal structure.
In another category oF patients, relapse
was correlated with amplifcation at the
bcr-
abl
translocation. These results sug-
gest that while rationally designed drugs
like Gleevec may exhibit promising clin-
ical eFfcacy, the appearance oF resistance
could be a signifcant problem.
Gleevec also inhibits the c-kit tyrosine
kinase where activating mutations are
Found in gastrointestinal stromal tumors
(GIST), a tumor Frequently reFractory to
chemotherapy. While a range oF other
tumors express c-kit, the encouraging
results oF the Gleevec Phase I study on
GIST suggest that its clinical application
may be wider than initially anticipated,
with the proviso that clinical resistance
may also appear in other indications.
4
The ErbB Family
The epidermal growth Factor (EG±) Fam-
ily oF tyrosine kinase receptors (the ErbB
receptors) play a crucial role in regulating
proliFeration. In tumor cells, a variety oF
mutagenic events give rise to increased
ErbB activity, including gene amplifca-
tion and mutations that alter protein
stability.
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