152
U N I T 1
Cell and Tissue Function
humanized
antibodies in which the murine regions that
bind antigen have been grafted into human immunoglobu-
lin (Ig) Gmolecules, and
entirely human
antibodies derived
from transgenic mice expressing immunoglobulin genes.
65
Some monoclonal antibodies are directed to block major
pathways central to tumor cell survival and proliferation,
whereas others are modified to deliver toxins, radioiso-
topes, cytokines, or other cancer drugs.
Currently approved monoclonal antibodies include
rituximab (Rituxan), a chimeric IgG monoclonal anti-
body that targets the CD20 antigen on B cells and is
used in the treatment of nonHodgkin lymphoma; beva-
cozumab (Avastin), a humanized IgG monoclonal anti-
body that targets vascular endothelial growth factor
(VEGF) to inhibit blood vessel growth (angiogenesis)
and is approved for treatment of colorectal, lung, renal,
and breast cancer; and cetuximab (Erbitux), a chimeric
monoclonal antibody that targets the epidermal growth
factor receptor (EGFR) to inhibit tumor cell growth and
is approved for treatment of colorectal cancer and squa-
mous cell cancer of the head and neck.
64,65
Cytokines.
The biologic response modifiers include
cytokines such as the interferons and interleukins. The
interferons
appear to inhibit viral replication and also
may be involved in inhibiting tumor protein synthesis,
prolonging the cell cycle, and increasing the percentage
of cells in the G
0
phase. Interferons stimulate NK cells
and T-lymphocyte killer cells. There are three major
types of interferons, alpha (
α
), beta (
β
), and gamma (
γ
),
with members of each group differing in terms of their
cell surface receptors.
63
Interferon-
γ
has been approved
for the treatment of hairy cell leukemia, AIDS-related
Kaposi sarcoma, and chronic myelogenous leukemia,
and as adjuvant therapy for patients at high risk for
recurrent melanoma. Interferon-
α
has been used to treat
some solid tumors (e.g., renal cell carcinoma, colorectal
cancer, carcinoid tumors, ovarian cancer) and hema-
tologic neoplasms (e.g., B-cell and T-cell lymphomas,
cutaneous T-cell lymphoma, and multiple myeloma).
62
Research now is focusing on combining interferons with
other forms of cancer therapy and establishing optimal
doses and treatment protocols.
The
interleukins
(ILs) are cytokines that provide com-
munication between cells by binding to receptor sites on
the cell surface membranes of the target cells. Of the 18
known interleukins (see Chapter 15), IL-2 has been the
most widely studied. A recombinant human IL-2 (rIL-2,
aldesleukin) has been approved by the U.S. Food and
Drug Administration (FDA) and is currently being used
for the treatment of metastatic renal cell carcinoma and
metastatic melanoma.
63
Adjuvants.
Adjuvants are substances such as Bacillus
Calmette-Guérin (BCG) that nonspecifically stimulate or
indirectly augument the immune system.
63
Instillations
of BCG, an attenuated strain of the bacterium that
causes bovine tuberculosis, are used to treat noninva-
sive bladder cancer after surgical ablation. It is assumed
that BCG acts locally to stimulate an immune response,
thereby decreasing the relapse rate.
TargetedTherapy
Researchers have been working diligently to produce drugs
that selectively attack malignant cells while leaving normal
cells unharmed.
66,67
The characteristics and capabilities
of cancer cells have been used to establish a framework
for the development of such targeted therapies, including
those that disrupt molecular signaling pathways, inhibit
angiogenesis, and harness the body’s immune system. The
first targeted therapies were the monoclonal antibodies.
Researchers are now working to design drugs that can dis-
rupt molecular signaling pathways, such as those that use
the protein tyrosine kinases. The protein tyrosine kinases
are intrinsic components of the signaling pathways for
growth factors involved in the proliferation of lymphocytes
and other cell types. Imatinib mesylate is a protein tyro-
sine kinase inhibitor indicated in the treatment of chronic
myeloid leukemia (see Chapter 11). Angiogenesis is also
being explored as a target for targeted cancer therapy.
66
One of the newerr antiangiogenic agents, bevacizumab,
targets and blocks VEGF, which is released by many can-
cers to stimulate proliferation of new blood vessels.
SUMMARY CONCEPTS
■■
The methods used in the detection and diagnosis
of cancer vary with the type of cancer and its
location. Because many cancers are curable if
diagnosed early, health care practices designed
to promote early detection, such as screening, are
important.
■■
Diagnostic methods include laboratory tests for
the presence of tumor markers, cytologic and
histologic studies using cells or tissue specimens,
and gene profiling methods, in addition to
medical imaging.
■■
There are two basic methods of classifying
tumors: grading according to the histologic
or tissue characteristics, and clinical staging
according to spread of the disease.TheTumor,
Node, Metastasis (TNM) system for clinical
staging of cancer uses tumor size, lymph node
involvement, and presence of metastasis.
■■
Treatment of cancer can include surgery,
radiation, or chemotherapy. Other therapies
include hormonal, immunologic, and biologic
therapies, as well as molecularly targeted agents
that disrupt molecular signaling pathways, inhibit
angiogenesis, and harness the body’s immune
system.Treatment plans that use more than one
type of therapy are providing cures for a number
of cancers that a few decades ago had a poor
prognosis, and are increasing the life expectancy
in other types of cancer.
