Biomedical Engineering Reference
In-Depth Information
single cell if not for genome instability. Genome instability is caused by mutations of DNA repair/
checkpoint surveillance mechanisms that normally results in cell cycle arrest until damaged DNA
has been repaired, or in case DNA cannot be efi ciently repaired results in elimination of the cell
via apoptosis. The genome guarding protein p53 as well as proteins sensing DNA damage such
as ATR, ATM, and their downstream signal kinases Chk1 and Chk2 play important roles in such
checkpoints, and their loss often precedes genome instability.
One of the main obstacles in cancer therapy is tumor heterogeneity that is closely related to
genome instability. Within one tumor several different subpopulations of tumor stem cells often
exist, due to accelerated chromosomal aberrations driven by genome instability resulting in chro-
mosomal deletions, duplications and translocations. Consequently, while i rst line chemotherapy
does often lead to good responses and tumor regression, tumor heterogeneity makes it very difi cult
to kill all tumor cells within a tumor. Consequently, some cancer cells may be inherently resis-
tant toward a given drug due to mutation of its primary target/receptor or due to dysregulation of
downstream signal transduction cascades. Such cells will often continue to divide and will eventu-
ally overgrow the drug sensitive cells resulting in a new tumor that is now resistant. As a result in
modern anticancer therapy, combinations of several (i ve or more) different drugs targeting different
receptors/pathways are often used.
23.1.4 A
NTICANCER
A
GENTS
Despite intensive research aimed at understanding the molecular pathology of cancer, a great
deal of anticancer agents currently in clinical use were discovered and even entered the clinic
before their exact mechanism of action was clarii ed. These drugs were often discovered in cellular
screens of extracts from natural sources, or in in vivo screens using a leukemic P388 mouse model.
The drugs discovered typically inhibit DNA synthesis (antimetabolites), damage DNA (DNA alky-
lating agents and topoisomerase poisons), or inhibit the function of the mitotic microtubule-based
spindle apparatus (taxanes) (Table 23.1). The reason for these agents still being in clinical use
relates to the fact that they are often highly effective although they have toxic properties toward
normal fast proliferating cells as the intestinal and gut lining hair follicles, and the bone marrow
cells, leading to the well-known effects of classical chemotherapy including nausea, vomiting, hair
loss, and myleosuppression. The cytotoxics stands in contrast to the so-called targeted therapies
that are developed in a totally different fashion by applying knowledge concerning the structure of
a primary target with molecular in silico screening as well as high-throughput compound library
screening, or by designing protein-based medications, which in the case of cancer treatment are
often in the form of cell surface tyrosine kinase antagonistic antibodies. Examples of targeted ther-
apeutic anticancer agents are kinase inhibitors (Gleevec, Iressa), proteasome inhibitors (Velcade),
histone deacetylase (HDAC) inhibitors (Zolinza, belinostat), and antibodies against cell surface
receptors (Herceptin) (Table 23.1).
23.2 ANTICANCER AGENTS CURRENTLY USED
Reviewing the multitude of anticancer agents in current use is an overwhelming task and not
within the scope of this chapter. Instead, we will describe the development and mechanism of
action of three classic cytotoxics. Two antimetabolites Xeloda and Alimta inhibiting the pro-
duction of precursors for DNA synthesis in the cell, as well as an agent targeting the structural
protein
-tubulin (Paclitaxel) involved in microtubule functioning. We will likewise review the
development and mechanism of three new classes of anticancer therapeutics, the HDAC inhibi-
tors exemplii ed by Zolinza, the kinase inhibitors exemplii ed by the BCR-ABL tyrosine kinase
inhibitor Gleevec, and i nally the HER2/Neu tyrosine kinase antagonist monoclonal antibody
Herceptin (Table 23.1).
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