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

General Principles of Cancer
Chemotherapy
Bruce A. Chabner
Introduction. The practice of cancer medicine has
changed dramatically as curative treatments have been
identified for many previously fatal malignancies such
as testicular cancer, lymphomas, and leukemia.
Adjuvant chemotherapy and hormonal therapy can
extend life and prevent disease recurrence following
surgical resection of localized breast, colorectal, and
lung cancers. Chemotherapy is also employed as part
of the multimodal treatment of locally advanced head
and neck, breast, lung, and esophageal cancers, softtissue
sarcomas, and pediatric solid tumors, thereby
allowing for more limited surgery and even cure in
these formerly incurable cases. Colony-stimulating factors
restore bone marrow function and expand the utility
of high-dose chemotherapy. Chemotherapeutic
drugs are increasingly used in nonmalignant diseases:
cytotoxic antitumor agents have become standard in
treating autoimmune diseases, including rheumatoid
arthritis (methotrexate and cyclophosphamide), Crohn’s
disease (6-mercaptopurine), organ transplantation
(methotrexate and azathioprine), sickle cell anemia
(hydroxyurea), and psoriasis (methotrexate). Despite
these therapeutic successes, few categories of medication
have a narrower therapeutic index and greater
potential for causing harmful effects than the cytotoxic
antineoplastic drugs. A thorough understanding of their
pharmacology, including drug interactions and clinical
pharmacokinetics, is essential for their safe and effective
use in humans.
The compounds used in the chemotherapy of
neoplastic disease are quite varied in structure and mechanism
of action, including alkylating agents; antimetabolite
analogs of folic acid, pyrimidine, and purine; natural
products; hormones and hormone antagonists; and a
variety of agents directed at specific molecular targets.
Tables 60-1 through 60-5 summarize of the main classes
and examples of these drugs. Figure 60–1 depicts the
cellular targets of chemotherapeutic agents.
The strategy for the discovery of anticancer drugs
has undergone a dramatic transformation in the past 15
years, based largely on advances in understanding the
molecular basis of malignant transformation. In prior
years, cancer drugs were discovered through the largescale
testing of synthetic chemicals and natural products
against rapidly proliferating animal tumor
systems, primarily murine leukemias (Chabner and
Roberts, 2005). Most of the agents discovered in these
screens interacted with DNA or its precursors, inhibiting
the synthesis of new genetic material and causing
broad-based damage to DNA in both normal and
malignant cells. The rapidly expanding knowledge of
cancer biology has led to the discovery of entirely new
and more cancer-specific targets (e.g., growth factor
receptors, intracellular signaling pathways, epigenetic
processes, tumor vascularity, DNA repair defects, and
cell death pathways). For example, in many tumors,
proliferation and survival depends on the constitutive
activity of a single growth factor pathway, or so-called
oncogene addiction (i.e., the “Achilles heel”), and inhibition
of that pathway leads to cell death (Weinstein
and Joe, 2006). Thus, imatinib (GLEEVEC) attacks the
unique and specific bcr-abl translocation in chronic
myelocytic leukemia. Imatinib also inhibits c-kit and
produces extended control of gastrointestinal stromal
tumors that express a mutated and constitutively activated
form of c-kit. Monoclonal antibodies effectively
inhibit tumor-associated antigens such as the amplified
her-2/neu receptor in breast cancer cells. These examples
emphasize that entirely new strategies for drug
discovery and development, and advances in patient
care, will result from new knowledge of cancer biology.
Figure 60–1 outlines the common targets of cancer