Biomedical Engineering Reference
In-Depth Information
reversible cell cycle arrest. This difference, that is at present poorly understood, is believed to play
a role in the cancer selectivity of HDAC inhibitors. In addition, by reprogramming gene expression
HDAC inhibitors can cause redifferentiation of leukemic cells, underscoring their utility in the
treatment of hematological malignancies. During recent years, the HDACs have been found to have
targets other than histones. These include p53,
-tubulin, and many transcription factors. Some of
the cellular effects of HDAC inhibition are related to such nonhistone targets.
Although HDAC inhibitors have been shown to have anticancer activity on their own, their main
strength will likely be as part of drug combinations. Preclinical studies and emerging clinical stud-
ies as well, point toward HDAC inhibitors being capable of increasing the efi cacy and broaden the
therapeutic window of several classes of unrelated anticancer compounds such as the topoisomerase
I poisons (irinotecan, topotecan), the topoisomerase II poisons (etoposide, doxorubicin daunoru-
bicin), the antimetabolite (5-FU), retinoic acids, the proteasome inhibitor Velcade, and the kinase
inhibitor Gleevec and the others as well.
α
23.2.5 G
LEEVEC
Imatinib or Gleevec (see also Chapter 11) is a tyrosine kinase inhibitor developed by Novartis,
which has greatly improved the treatment of chronic myeloid leukemia (CML). CML is a rather rare
condition (prevalence is 1:100,000), which in about 90% of all cases is caused by a specii c chro-
mosomal translocation t(29;22) (q34;q11) also referred to as the Philadelphia chromosome. Through
the creation of this new chromosomal breakpoint, this translocation creates a unique fusion protein
BCR-ABL with oncogenic properties caused by its constitutive tyrosine kinase activity, which activates a
number of cellular pathways including JAK/STAT and Ras-Raf-Mek-MAPK leading to the achievement
of proliferation and antiapoptotic signaling as depicted in Figure 23.7A.
Receptor
Plasma membrane
Raf
Ras
MEK1/2
Cytoplasm
Mitochondrion
GRB2
SOS
SHC
BCL2
family
MAPK
pathway
CRKL
BCR-ABL
JAK/STAT
Proliferation
survival
diferentiation
SCR
Y177
P
Proliferation
JAK/STAT
Nucleus
(A)
FIGURE 23.7
(A) Cartoon highlighting pathways affected by the constitutive tyrosine kinase activity of the
BCR-ABL onco protein and its cellular consequences.
