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

1674 employed in traditional cytotoxic therapy, molecular
testing of tumors could improve outcomes by pairing
patients with drugs likely to be effective against mutations
that drive tumor proliferation or survival.
Mutations of the b-Raf, HER 2/neu, and Alk, which are
found in subsets of solid tumors in human subjects, represent
examples of promising targets for solid tumor
chemotherapy.
Inherited differences in protein sequence polymorphisms
or levels of RNA expression influence toxicity
and anti-tumor response. For example, tandem
repeats in the promoter region of the gene encoding
thymidylate synthase, the target of 5-fluorouracil, determine
the level of expression of the enzyme. Increased
numbers of repeats are associated with increased gene
expression, a lower incidence of toxicity, and a
decreased rate of response in patients with colorectal
cancer (Pullarkat et al., 2001). Polymorphisms of the
dihydropyrimidine dehydrogenase gene, the product of
which is responsible for degradation of 5-fluorouracil,
are associated with decreased enzyme activity and a
significant risk of overwhelming drug toxicity, particularly
in the rare individual homozygous for the polymorphic
genes (Van Kuilenburg et al., 2002). Other
polymorphisms appear to affect the clearance and therapeutic
activity of cancer drugs, including tamoxifen
(Schroth et al., 2007), methotrexate, irinotecan, and 6-
mercaptopurine (Cheok and Evans, 2006).
Other aspects of molecular biology are entering
into clinical decision making in oncology. Gene expression
profiling, in which the levels of messenger RNA
from thousands of genes are randomly surveyed using
gene arrays, has revealed tumor profiles that are highly
associated with metastasis (Ramaswamy et al., 2003).
The expression of the transcription factor HOX B13
correlates with disease recurrence in patients receiving
adjuvant hormonal therapy in breast cancer (Ma et al.,
2004). Gene expression profiles also predict the benefit
of adjuvant chemotherapy for breast cancer patients
(Sotiriou and Pusztai, 2009) and the response of ovarian
cancer patients to platinum-based therapy
(Dressman et al., 2007).
New molecular tests and their more widespread
use likely will shorten the time for drug development
and approval, realize savings by avoiding the cost and
toxicity of ineffective drugs, and ultimately improve
patient outcome (Chabner and Roberts, 2005; Roberts
and Chabner, 2004). Undoubtedly, molecular testing
to select patients for specific treatments will be a cornerstone
of cancer chemotherapy for years to come.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
A Cautionary Note. Although advances in drug discovery
and molecular profiling of tumors offer great promise for
improving the outcomes of cancer treatment, a final word
of caution regarding all treatment regimen deserves
emphasis. The pharmacokinetics and toxicities of cancer
drugs vary among individual patients. It is imperative
to recognize toxicities early, to alter doses or discontinue
offending medication to relieve symptoms and reduce
risk, and to provide vigorous supportive care (platelet
transfusions, antibiotics, and hematopoietic growth factors).
Toxicities affecting the heart, lungs, or kidneys may
be irreversible if recognized late in their course, leading
to permanent organ damage or death. Fortunately, such
toxicities can be minimized by early recognition and by
adherence to standardized protocols and to the guidelines
for drug use.
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