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

classification as anti-angiogenics is convenient but tentative.
Thalidomide originally entered development in
the 1950s for the treatment of pregnancy-associated
morning sickness but was withdrawn from the market
due to the tragic consequences of teratogenicity and
dysmelia (stunted limb growth) (Franks et al., 2004). It
re-entered clinical practice, initially because of its clinical
efficacy in erythema nodosum leprosum, for which
it received approval in 1998 (see Chapter 56). Further
research revealed its anti-angiogenic and immunomodulatory
effects, and these findings triggered experimental
trials in cancer, most notably against multiple
myeloma (MM). Both thalidomide and lenalidomide
possess potent activity in newly diagnosed and heavily
pretreated relapsed/refractory MM patients (Richardson
et al., 2007). Lenalidomide also has striking clinical
activity in the 5q− subset of myelodysplastic syndrome
(MDS) and has been approved for this indication. A
specific gene array profile identifies MDS patients who
lack the 5q− abnormality but respond to lenalidomide
(Ebert et al., 2008).
O
N
O
O
∗
THALIDOMIDE
NH
∗ Denotes the chiral center.
O
NH 2
O O H
N
LENALIDOMIDE
Mechanisms of Action. The precise mechanisms
responsible for these drugs’ clinical effects are unclear.
Thalidomide’s enantiomeric interconversion and spontaneous
cleavage to multiple short-lived and poorly
characterized metabolites, as well as its species-specific
in vivo metabolic activation, confound the interpretation
of preclinical in vitro and in vivo mechanistic studies.
At least four distinct, but potentially complementary,
mechanisms have been proposed to explain the antitumor
activity of IMiDs (Figure 62–3):
• Direct anti-proliferative/pro-apoptotic antitumor
effects. They inhibit the anti-apoptotic effects of NFκB
and the anti-apoptotic Bcl-2 family member
A1/Bfl-1 (Mitsiades et al., 2002a).
• Indirect inhibition of tumor cell growth and survival
by abrogation of cell interactions with adhesion molecules
(Hideshima et al., 2000).
• Inhibition of interleukin-6 (IL-6) and tumor necrosis
factor α (TNF α) production, release, and signaling,
leading to anti-angiogenic effects.
N
∗
O
NK cell
production
and
functionality
Adhesion
B
Tumor
cell
IL-6
IL-2
+
INF-γ
T cell
NK Cell
Bone marrow stroma
Anti-apoptosis
cell growth
A1/Bfl-1
NFκ-B
IL-6
Angiogenesis
IL-6 SDF-1α
IGFL bFGF
VEGF TNFα
Capillary
endothelium
Figure 62–3. Schematic overview of proposed mechanisms of
antimyeloma activity of thalidomide and its derivatives. Some
biological hallmarks of the malignant phenotype are indicated
in light-blue boxes. The proposed sites of action for thalidomide
(letters inside red and green circles) are hypothesized to also be
operative for thalidomide derivatives. A. Direct anti–multiple
myeloma (MM) effect on tumor cells, including G 1
growth arrest
and/or apoptosis, even against MM cells resistant to conventional
therapy. This is due to the disruption of the anti-apoptotic effect
of BCL-2 family members, blocking NF-κB signaling, and inhibition
of the production of interleukin-6 (IL-6). B. Inhibition of
MM-cell adhesion to bone marrow stromal cells partially due to
the reduction of IL-6 release. C. Decreased angiogenesis due to
the inhibition of cytokine and growth factor production and
release. D. Enhanced T-cell production of cytokines, such as IL-2
and interferon-γ (IFN-γ), that increase the number and cytotoxic
functionality of natural killer (NK) cells. VEGF, vascular
endothelial growth factor.
• Immunomodulation through enhancement of natural
killer (NK) and T cell–mediated cytotoxicity.
Their antagonism of anti-apoptotic pathways and
their anti-angiogenic effects could account for the
clinical synergy with glucocorticoids and bortezomib
against MM (Mitsiades et al., 2002b).
Thalidomide
Pharmacokinetics and Therapeutic Use. Thalidomide (THALOMID)
exists at physiological pH as a racemic mixture of cell-permeable
D
C
A
1741
CHAPTER 62
TARGETED THERAPIES: TYROSINE KINASE INHIBITORS, MONOCLONAL ANTIBODIES, AND CYTOKINES