DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

reduced to 5 mg daily for patients with moderate hepatic impairment
(Child-Pugh class B); guidelines for dose reduction of temsirolimus
in such patients have not been established. The drugs’
pharmacokinetics do not depend on renal function, and hemodialysis
does not hasten temsirolimus clearance.
Higher-dose intravenous temsirolimus regimens, up to
175 mg/week, have been explored in mantle cell lymphoma and in
other diseases, as has oral temsirolimus administration. Poor oral
bioavailability hampers the oral route of administration, as <20% of
drug or active metabolite reaches the plasma (Buckner et al., 2010).
Clinical Toxicity. The rapamycin analogs have very similar patterns
of toxicity. The most prominent side effects are a mild maculopapular
rash, mucositis, anemia, and fatigue, each occurring in 30-50%
of patients. A minority of patients will develop leukopenia or thrombocytopenia
with progressive cycles of treatment, and these effects
are reversed if therapy is discontinued. Less common side effects
include hyperglycemia, hypertriglyceridemia, and, rarely, pulmonary
infiltrates and interstitial lung disease. Pulmonary infiltrates emerge
in 8% of patients receiving everolimus and in a smaller percentage
of those treated with temsirolimus. In patients showing minor radiological
changes, but without symptoms, drug administration may be
continued. If symptoms such as cough or shortness of breath develop
or radiological changes progress, the drug should be discontinued.
Prednisone may hasten the resolution of radiological changes and
symptoms (Hutson et al., 2008).
BIOLOGICAL RESPONSE MODIFIERS
Biological response modifiers include cytokines or
monoclonal antibodies that beneficially affect the
patient’s biological response to a neoplasm. Included
are agents that act indirectly to mediate their antitumor
effects (e.g., by enhancing the immunological response
to neoplastic cells) or directly, binding to receptors on
the tumor cells and delivering toxins or radionuclides.
Recombinant DNA technology has greatly facilitated
the identification and production of a number of human
proteins with potent effects on the function and growth
of both normal and neoplastic cells. Proteins that currently
are in clinical use include the interferons (see
Chapters 35 and 58); interleukins (see Chapter 35);
hematopoietic growth factors such as erythropoietin,
filgrastim [granulocyte colony-stimulating factor (G-
CSF)], and sargramostim [granulocyte-macrophage
colony-stimulating factor (GM-CSF)] (see Chapter 37);
and monoclonal antibodies.
Monoclonal Antibodies
Since the discovery of methods for fusing mouse
myeloma cells with B lymphocytes, it has been possible
to produce a single species of murine antibody that
recognizes a specific antigen. Cancer cells express antigens
that are attractive targets for monoclonal antibody–based
therapy (Table 62–1). Immunization of
mice with human tumor cell extracts has led to the isolation
of monoclonal Abs reactive against unique or
highly expressed target antigens, and a few of these
monoclonals possess antitumor activity. Because
murine antibodies have a short t 1/2
in humans, activate
human immune effector mechanisms poorly, and
induce a human anti-mouse antibody immune response,
they usually are chimerized by substituting major portions
of the human IgG molecule. Presently, monoclonal
antibodies have received FDA approval for
lymphoid and solid tumor malignancies. Available
agents include rituximab (Coiffier et al., 2002) and
alemtuzumab (Keating et al., 2002) for lymphoid
malignancies, trastuzumab (Vogel et al., 2002) for
breast cancer, bevacizumab (Sandler et al., 2006) for
colon and lung cancer, and cetuximab and panitumumab
(Van Cutsem et al., 2007) for colorectal cancer
and head and neck cancer. The nomenclature adopted
for naming therapeutic monoclonal antibodies is to terminate
the name in -ximab for chimeric antibodies and
-umab for fully humanized antibodies.
Unmodified monoclonal antibodies may kill tumor
cells by a variety of mechanisms [e.g., antibody-dependent
cellular cytotoxicity (ADCC), complement-dependent
cytotoxicity (CDC), and direct induction of apoptosis by
antigen binding], but the clinically relevant mechanisms
for most antibodies are uncertain (Villamor et al., 2003).
Monoclonal antibodies also may be linked to a toxin
(immunotoxins), such as gemtuzumab ozogamicin
(MYLOTARG) (Larson et al., 2005) or denileukin diftitox
(ONTAK) (Negro-Vilar et al., 2007), or conjugated to a
radioactive isotope, as in the case of 90 Yttrium ( 90 Y)-
ibritumomab tiuxetan (ZEVALIN) (Witzig et al., 2002)
(Table 62–1). Genetic polymorphisms affecting the target
antigen or complement receptors may influence response
(Cartron et al., 2002).
Unarmed Monoclonal Antibodies
Rituximab. Rituximab (RITUXAN) is a chimeric monoclonal
antibody that targets the CD20 B-cell antigen
(Tables 62–1 and 62–2) (Maloney et al., 1997). CD20
is found on cells from the pre–B cell stage through its
terminal differentiation to plasma cells and is expressed
on 90% of B-cell neoplasms. The biological functions
of CD20 are uncertain, although incubation of B cells
with anti-CD20 antibody has variable effects on cellcycle
progression, depending on the monoclonal antibody
type. Monoclonal antibody binding to CD20
generates transmembrane signals that produce
autophosphorylation and activation of serine/tyrosine
protein kinases, induction of c-myc oncogene expression,
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CHAPTER 62
TARGETED THERAPIES: TYROSINE KINASE INHIBITORS, MONOCLONAL ANTIBODIES, AND CYTOKINES