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Journal reading

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. Introduction Structure and pharmacokinetics of thalidomide Development of thalidomide analogues Role of thalidomide in cancer prevention

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Journal reading

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  1. 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

  2. Introduction • Structure and pharmacokinetics of thalidomide • Development of thalidomide analogues • Role of thalidomide in cancer prevention • Thalidomide in the management of the premalignant conditions of oral cavity • Potential role of thalidomide in the prevention and management of oral cancer • Conclusions

  3. Introduction • Structure and pharmacokinetics of thalidomide • Development of thalidomide analogues • Role of thalidomide in cancer prevention • Thalidomide in the management of the premalignant conditions of oral cavity • Potential role of thalidomide in the prevention and management of oral cancer • Conclusions

  4. 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. Introduction • Structure and pharmacokinetics of thalidomide • Development of thalidomide analogues • Role of thalidomide in cancer prevention • Thalidomide in the management of the premalignant conditions of oral cavity • Potential role of thalidomide in the prevention and management of oral cancer • Conclusions

  9. 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

  11. Introduction • Structure and pharmacokinetics of thalidomide • Development of thalidomide analogues • Role of thalidomide in cancer prevention • Thalidomide in the management of the premalignant conditions of oral cavity • Potential role of thalidomide in the prevention and management of oral cancer • Conclusions

  12. 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. Introduction • Structure and pharmacokinetics of thalidomide • Development of thalidomide analogues • Role of thalidomide in cancer prevention • Thalidomide in the management of the premalignant conditions of oral cavity • Potential role of thalidomide in the prevention and management of oral cancer • Conclusions

  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. Introduction • Structure and pharmacokinetics of thalidomide • Development of thalidomide analogues • Role of thalidomide in cancer prevention • Thalidomide in the management of the premalignant conditions of oral cavity • Potential role of thalidomide in the prevention and management of oral cancer • Conclusions

  17. Oral lichen planus • Considered as a potentially malignant disease b. Erosive form is more prone to the development of OSCC

  18. Chronic discoid lupus erythematosus • 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

  19. 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

  20. Introduction • Structure and pharmacokinetics of thalidomide • Development of thalidomide analogues • Role of thalidomide in cancer prevention • Thalidomide in the management of the premalignant conditions of oral cavity • Potential role of thalidomide in the prevention and management of oral cancer • Conclusions

  21. 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-

  22. 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

  23. 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)

  24. Yang et al 2009  (animal experiments) • The chemopreventive effect of thalidomide on DMBA-induced oral carcinogenesis in hamsters with respect to angiogenesis

  25. Thalidomide significantly decreased the squamous cell carcinoma (SCC) incidence from 57.9% to 11.8% • Thalidomide significantly decreasedmicrovessel density in papilloma and SCC • The geneexpression of VEGF andTNF- was down-regulated

  26. Thalidomide incombination with chemotherapeutics might be more effectivethan single use of thalidomide

  27. Myoung et al2001  • 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

  28. 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

  29. Suggested that Thalidomide use alone is not likely to be effective for the treatment of OSCC  Might be regarded as adjuvant chemotherapeuticstrategy

  30. 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

  31. 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

  32. Introduction • Structure and pharmacokinetics of thalidomide • Development of thalidomide analogues • Role of thalidomide in cancer prevention • Thalidomide in the management of the premalignant conditions of oral cavity • Potential role of thalidomide in the prevention and management of oral cancer • Conclusions

  33. 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

  34. Certain problems that deserve further investigation  • The number and sample size of present clinical researches are too small to powerful support 2. No clinical trial oral cancer has been available

  35. 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

  36. Thank you for your attention

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