Transcript Mechanisms of antitumor activity

Journal reading
報告者：PGY2 曾智皇
報告日期 : 103.05.13
指導老師 : 林立民 醫師
陳玉昆 醫師
1. Introduction
2. Structure and pharmacokinetics of
thalidomide
3. Development of thalidomide analogues
4. Role of thalidomide in cancer prevention
5. Thalidomide in the management of the
premalignant conditions of oral cavity
6. Potential role of thalidomide in the
prevention and management of oral cancer
7. Conclusions
1. Introduction
2. Structure and pharmacokinetics of
thalidomide
3. Development of thalidomide analogues
4. Role of thalidomide in cancer prevention
5. Thalidomide in the management of the
premalignant conditions of oral cavity
6. Potential role of thalidomide in the
prevention and management of oral cancer
7. Conclusions
Introduction
• Oral cancer is a major malignancy leading to
great morbidity and mortality rates worldwide
in decades
• The 5-year survival rate for oral cancer has not
improved remarkably over the past several
years
• Angiogenesis and tumour-associated
inflammatory response
 tumorigenesis, aggressive behaviour
and metastatic potential of various solid
tumours
• Thalidomide was introduced in the 1950s
by a West German company
 morning sickness during pregnancy
• Quickly overshadowed  teratogenic
effect (phocomelia)
• Resurrected for autoimmune or inflammatory
basis and cancers
 erythema nodosum leprosum, pmrigo
nodularis, actinic pmrigo, Behcet’s syndrome,
graft-versus-host disease, myelodysplastic
syndrome, multiple myeloma and some solid
tumours
• Approved in the USA for cutaneous
manifestations of lepromatous leprosy
• Disorders of oral cavity, such as aphthous
stomatitis, Crohn’s disease and HIV-related
Kaposi’s sarcoma were sensitive to thalidomide
• Its effects on OSCC cells in vitro and in vivo
which show that thalidomide might be a
potential agent to prevent and treat oral cancer
1. Introduction
2. Structure and pharmacokinetics of
thalidomide
3. Development of thalidomide analogues
4. Role of thalidomide in cancer prevention
5. Thalidomide in the management of the
premalignant conditions of oral cavity
6. Potential role of thalidomide in the
prevention and management of oral cancer
7. Conclusions
• Known as a-(N-phthalimido) glutarimid
• It contains a phthalimide ring and a
glutarimide ring with an asymmetric carbon
• Racemic mixture of dextrorotatory (R) and
levorotatory (S) forms in a ratio of 1:1
• Thalidomide undergoes rapid spontaneous
non-enzymatic hydrolytic degradation in
biological fluids
• Temperature and pH affect the rate of
hydrolysis
• Chronic administration
 not inhibit or stimulate its own metabolism
or that of other drugs
• Elimination half-life of thalidomide is 4.7 h
1. Introduction
2. Structure and pharmacokinetics of
thalidomide
3. Development of thalidomide analogues
4. Role of thalidomide in cancer prevention
5. Thalidomide in the management of the
premalignant conditions of oral cavity
6. Potential role of thalidomide in the
prevention and management of oral cancer
7. Conclusions
Development of thalidomide
analogues
• Enhanced anticancer activity, while lacking the
toxicity of the parent drug
• Immunomodulatory drugs (IMiDs) and
Selective cytokine inhibitory drugs (SelCIDs)
have been regarded as two types of
thalidomide analogues
1. Introduction
2. Structure and pharmacokinetics of
thalidomide
3. Development of thalidomide analogues
4. Role of thalidomide in cancer prevention
5. Thalidomide in the management of the
premalignant conditions of oral cavity
6. Potential role of thalidomide in the
prevention and management of oral cancer
7. Conclusions
Role of thalidomide in cancer
prevention
Antitumor application
• Significant impact on the treatment for nonsolid malignancies
 multiple myeloma and myelodyplastic disorders
Mechanisms of antitumor activity
1. Introduction
2. Structure and pharmacokinetics of
thalidomide
3. Development of thalidomide analogues
4. Role of thalidomide in cancer prevention
5. Thalidomide in the management of the
premalignant conditions of oral cavity
6. Potential role of thalidomide in the
prevention and management of oral cancer
7. Conclusions
Oral lichen planus
a. Considered as a potentially malignant disease
b. Erosive form is more prone to the
development of OSCC
Chronic discoid lupus erythematosus
a. A mucocutaneous autoimmune
disease
b. May develop malignant
transformation
c. Immunosuppressive activity of
thalidomide has been applied to the
treatment, especially which
insensitive to routine therapy
• Efficacy of low-dose thalidomide therapy of
CDLE
 alternative choice in cases resistant to the
usual treatment
• Mechanisms involved in clinical use of
thalidomide for OLP and CDLE are still limited
 its ability to decrease production of TNF-a
1. Introduction
2. Structure and pharmacokinetics of
thalidomide
3. Development of thalidomide analogues
4. Role of thalidomide in cancer prevention
5. Thalidomide in the management of the
premalignant conditions of oral cavity
6. Potential role of thalidomide in the
prevention and management of oral cancer
7. Conclusions
• The pathogenesis of oral cancer was proved to
be impairing T-cell activation and induction of
TNF-a
 anti-angiogenic effects and inhibition of
TNF-
Yang et al 2011 
• Effects of thalidomide on cell growth and
apoptosis in the human OSCC cell lines CAL27,
SCC4 and SCC9
• Thalidomide decreased the viability of CAL27
cells
• The results of flow cytometric analysis
indicated that treatment of OSCC cells for 72 h
with 100 g/ml thalidomide induced about
65% apoptosis
• After treatment of thalidomide for 24 h in
CAL27 and SCC4 cells, expression of TRAIL was
markedly increased (5.73-fold)
Yang et al 2009  (animal experiments)
• The chemopreventive effect of thalidomide on
DMBA-induced oral carcinogenesis in
hamsters with respect to angiogenesis
• Thalidomide significantly decreased the
squamous cell carcinoma (SCC) incidence from
57.9% to 11.8%
• Thalidomide significantly decreased
microvessel density in papilloma and SCC
• The gene expression of VEGF and TNF- was
down-regulated
• Thalidomide in combination with
chemotherapeutics might be more effective
than single use of thalidomide
Myoung et al 2001 
• Studied anti-tumour and anti-angiogenic
effect of paclitaxel and thalidomide on the
xenotransplanted OSCC of nude mice
• Tumor mass reached 300–500 mm3
thalidomide (200 mg/kg) and paclitaxel (13
mg/kg) were administered into the animals
tumor volume change was checked
• Evaluated 
a. VEGF expression and the expression of its
mRNA
b. CD31 for vessel density
• Thalidomide revealed lowered remarkably
VEGF expression and CD31 as well as VEGF
mRNA
not show significant inhibitory effect on the
tumour growth
• Suggested that
 Thalidomide use alone is not likely to be
effective for the treatment of OSCC
 Might be regarded as adjuvant
chemotherapeutic strategy
Vasvari et al 2007 
• Thalidomide in treatment of a xenotransplant
mouse model characteristic for advanced
head and neck SCCs
• Thalidomide alone was ineffective
• A combined treatment with low-dose cisplatin
inhibited significant tumour growth,
proliferationand angiogenesis
• Up to date, no clinical trial has assessed the
effect of thalidomide alone or combination
with other chemotherapeutics in the
treatment for oral cancer
• The studies have given us the hint of its
anticancer potential
1. Introduction
2. Structure and pharmacokinetics of
thalidomide
3. Development of thalidomide analogues
4. Role of thalidomide in cancer prevention
5. Thalidomide in the management of the
premalignant conditions of oral cavity
6. Potential role of thalidomide in the
prevention and management of oral cancer
7. Conclusions
• Potential therapeutic effects of thalidomide in
OLP and CDLE have been verified by clinical
trials
• Increasing evidences from in vitro and in vivo
experiments show that thalidomide is a
potential anticancerous agent for oral cancer
• Certain problems that deserve further
investigation 
1. The number and sample size of present
clinical researches are too small to powerful
support
2. No clinical trial oral cancer has been available
3. The tolerable level and time should be well
considered
4. The mechanisms involved in the therapeutic
effects of thalidomide, as well as drug
combination for oral diseases discussed above
are still unclear
Thank you for your
attention