Chapter 080. Cancer Cell Biology and Angiogenesis (Part 2) ppsx

Chapter 080. Cancer Cell Biology
and Angiogenesis
(Part 2)

Cancer Cell Biology
The treatment of most human cancers with conventional cytoreductive
agents has been unsuccessful due to the Gompertzian-like growth kinetics of solid
tumors (i.e., tumor growth is exponential in small tumors, with increasing
doubling times as tumors expand; since conventional chemotherapeutic agents
target proliferating cells, noncycling cells in large tumors are relatively resistant).
Genetic instability is inherent in most cancer cells and predisposes to the
development of intrinsic and acquired drug resistance. Thus, although tumors arise
from a single cell (i.e., they are clonal), large tumors become very heterogeneous
with multiple related subclones, some of which will be resistant to specific
therapies, leading to the selection of progressively more resistant tumors as
treatment progresses. Since a 1-cm tumor often contains 10
9
cells, and patients
typically present to their physicians with 10
10
–10
11
tumor cells, the obstacle to
curative treatment becomes more understandable. Rationally designed, target-
based therapeutic agents, directed against the specific molecular derangements that
distinguish malignant from nonmalignant cells, have become possible with
advances in the understanding of oncogene and tumor-suppressor pathways. This
chapter describes the convergence of scientific, pharmacologic, and medical
knowledge that has led to the targeted therapy of cancer.
Therapeutic Approaches to Cell Cycle Abnormalities in Cancer
The mechanism of cell division is substantially the same in all dividing

cells and has been conserved throughout evolution. The process assures that the
cell accurately duplicates its contents, especially its chromosomes. The cell cycle
is divided into four phases. During M-phase, the replicated chromosomes are
separated and packaged into two new nuclei by mitosis and the cytoplasm is
divided between the two daughter cells by cytokinesis. The other three phases of
the cell cycle are called interphase: G
1
(gap 1), during which the cell determines
its readiness to commit to DNA synthesis; S (DNA synthesis), during which the
genetic material is replicated and no re-replication is permitted; and G
2
(gap 2),
during which the fidelity of DNA replication is assessed and errors are corrected.
Deregulation of the molecular mechanisms controlling cell cycle
progression is a hallmark of cancer. Progression from one phase of the cell cycle
to the next is controlled by the orderly activation of cyclin-dependent kinases
(CDKs) that are regulated by signaling events that couple a cell's physiologic
response to its extracellular milieu. In normal cells, specific molecular signals,
called checkpoints, prevent progression into the next phase of the cell cycle until
all requisite physiologic processes are complete. Cancer cells often have defective
cell cycle checkpoints. The transition through G
1
into S-phase is a critical
regulator of cell proliferation, and the phosphorylation state of the retinoblastoma
tumor-suppressor protein (pRB) at the restriction point in late G
1
determines
whether a cell will enter S-phase. The complex of CDK4 or CDK6 with D type
cyclins forms a G
1

-specific kinase whose activity is regulated by growth factors,
nutrients, and cell-cell and cell-matrix interactions. Subsequent formation of an
active CDK2/cyclin E complex results in full phosphorylation of pRB, relieving its
inhibitory effects on the S-phase-regulating transcription factor E2F/DP1, and
permitting the activation of genes required for S-phase (such as dihydrofolate
reductase, thymidine kinase, ribonucleotide reductase, and DNA polymerase). The
activity of CDK/cyclin complexes can be blocked by CDK-inhibitors including
p21
Cip1/Waf1
, p16
Ink4a
, and p27
Kip1
, which block S-phase progression by preventing
the phosphorylation of pRB.
Genetic lesions that render the retinoblastoma pathway nonfunctional are
thought to occur in all human cancers. Loss of function of pRB as guardian of the
G
1
restriction point enables cancer cells to enter a mitotic cycle without the normal
input from external signals. Current therapeutic efforts to reverse the
derangements of the retinoblastoma pathway have taken two main approaches. All
kinases require the binding of ATP (and substrate) to the enzyme active site,
followed by transfer of the γ-phosphate to serine, threonine, or tyrosine residues of
the substrate. Flavopiridol was the first relatively selective CDK inhibitor
identified, with Ki or IC
50
s in the 40- to 400-nM range. Although flavopiridol was
initially thought to prevent tumor cell proliferation by inhibition of cell cycle
CDKs, it is now clear that regulation of cellular transcription elongation by the

CDK7/cyclin H and CDK9/cyclin T1 complexes may be the critical target of
flavopiridol. Phase II clinical trials of flavopiridol are in progress; responses have
been reported in chronic lymphocytic leukemia after a dosing schedule was
defined to optimize the pharmacokinetics of the drug. Laboratory efforts are
focused on the development of novel classes of CDK inhibitors capable of
specifically targeting individual CDK/cyclin complexes. A second therapeutic
endeavor to regain control of pRB function involves reversing the epigenetic
silencing of p16
Ink4a
gene and is discussed below.
p53, the "guardian of the genome," is a sequence-specific transcription
factor whose activity is regulated through tight control of p53 protein levels.
Normally, levels of p53 are kept low by its association with the mdm2 oncogene
product, which binds p53 and shuttles it out of the nucleus for proteolytic
degradation. p53 levels are regulated by two checkpoint pathways that are
activated in response to DNA damage or oncogene-induced cell proliferation (Fig.
80-1). The loss of p53 function abrogates these checkpoints and enables tumor
cells to escape cell cycle arrest, senescence, or apoptosis despite accumulation of
mutations and aberrant passage through the cell cycle.