Journal reading

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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

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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

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1. Introduction

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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

(5)

• 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)

(6)

• 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

(7)

• 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

(8)

1. Introduction

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• 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

(10)

• 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

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1. Introduction

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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

(13)

1. Introduction

(14)

Role of thalidomide in cancer prevention

Antitumor application

• Significant impact on the treatment for non- solid malignancies

 multiple myeloma and myelodyplastic disorders

(15)

Mechanisms of antitumor activity

(16)

1. Introduction

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Oral lichen planus

a. Considered as a potentially malignant disease b. Erosive form is more prone to the

development of OSCC

(18)

(19)

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

(20)

(21)

• 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

(22)

1. Introduction

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• 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-

(24)

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

(25)

• 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)

(26)

Yang et al 2009  (animal experiments)

• The chemopreventive effect of thalidomide on DMBA-induced oral carcinogenesis in

hamsters with respect to angiogenesis

(27)

• 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

(28)

• Thalidomide in combination with

chemotherapeutics might be more effective than single use of thalidomide

(29)

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

(30)

• 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

(31)

• Suggested that

 Thalidomide use alone is not likely to be effective for the treatment of OSCC

 Might be regarded as adjuvant chemotherapeutic strategy

(32)

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

(33)

• 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

(34)

1. Introduction

(35)

• 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

(36)

• 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

(37)

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

(38)

Journal reading

Journal reading

Introduction

Development of thalidomide analogues

Role of thalidomide in cancer prevention

Mechanisms of antitumor activity

Thank you for your

attention