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

6-MERCAPTOPURINE
6-THIOGUANINE
Inhibit purine ring biosynthesis
Inhibit DNA synthesis
ALIMTA
METHOTREXATE
Inhibit dihydrofolate reduction,
block thymidylate and
purine synthesis
CAMPTOTHECINS
ETOPOSIDE
TENIPOSIDE
DAUNORUBICIN
DOXORUBICIN
Block topoisomerase function
PROTEIN TYROSINE
KINASE INHIBITORS,
ANTIBODIES
Block activities of signaling pathways
Purine
synthesis
Enzymes
Drug resistance remains a major obstacle to successful
cancer treatment. Resistance results from a variety
of pharmacokinetic and molecular changes that can
defeat the best designed treatments, including poor drug
absorption and delivery; genetically determined variability
in drug transport, activation, and clearance; and mutations,
amplifications, or deletions in drug targets. The
resistance process is best understood for targeted
agents. Tumors developing resistance to bcr-abl
inhibitors and to inhibitors of the epidermal growth factor
receptor (EGFR) express mutations in the target
enzyme. Cells exhibiting drug-resistant mutations exist
in the patient prior to drug treatment and are selected by
drug exposure. Resistance to inhibitors of the EGFR
may develop through expression of an alternative receptor,
c-met, which bypasses EGFR blockade and stimulates
proliferation (Engelman et al., 2008). Defects in
recognition of DNA breaks and overexpression of
specific repair enzymes may also contribute to resistance
to cytotoxic drugs (Holleman et al., 2006), and a
Ribonucleotides
DNA
Proteins
Differentiation
Pyrimidine
synthesis
RNA
(transfer, messenger, ribosomal)
Deoxyribonucleotides
Microtubules
HYDROXYUREA
Inhibits ribonucleotide reductase
5-FLUOROURACIL
Inhibits thymidylate synthesis
GEMCITABINE
CYTARABINE
FLUDARABINE
2-CHLORODEOXYADENOSINE
CLOFARABINE
Inhibits DNA synthesis
PLATINUM ANALOGS
ALKYLATING AGENTS
MITOMYCIN
TEMOZOLOMIDE
Form adducts with DNA
L-ASPARAGINASE
Deaminates asparagine
Inhibits protein synthesis
EPOTHILONES
TAXANES
VINCA ALKALOIDS
ESTRAMUSTINE
Inhibit function of microtubules
ATRA
ARSENIC TRIOXIDE
HISTONE DEACELYASE INHIBITORS
Inducers of differentiation
Figure 60–1. Summary of the mechanisms and sites of action of some chemotherapeutic agents useful in neoplastic disease.
loss of apoptotic pathways can lead to resistance to both
cytotoxic and targeted agents.
In designing specific clinical regimens, a number
of factors must be considered. Drugs in combination
can negate the effects of a resistance mechanism specific
for a single agent, and they may be synergistic
because of their biochemical interactions. Ideally, drug
combinations should not overlap in their major toxicities.
In general, cytotoxic drugs are used as close as
possible to their maximally tolerated individual doses
and should be given as frequently as tolerated to discourage
tumor regrowth. Because the tumor cell population
in patients with clinically detectable disease
exceeds 1 g, or 10 9 cells, and each cycle of therapy kills
<99% of the cells, it is necessary to repeat treatments in
multiple, carefully timed cycles to achieve cure.
The Cell Cycle. An understanding of the life cycle of
tumors is essential for the rational use of antineoplastic
agents (Figure 60–2). Many cytotoxic agents act by
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CHAPTER 60
GENERAL PRINCIPLES OF CANCER CHEMOTHERAPY