THALIDOMIDE AND ITS ANALOGUES IN ANTICANCER THERAPY
ACTIVITY OF THALIDOMIDE AND IMIDS IN SOLID TUMORS
Phase II trials of thalidomide have shown potential activity against some solid tumors.[35,36,37] While the mechanism is unclear, it is thought to involve both immunomodulatory and non-immunomodulatory activities. These tumors produce immunologic suppressive factors that prevent priming and activation of CD4+ and CD8+ T cells of the lymph nodes.Other immune cells such as NK and macrophages are also inhibited and are therefore unable to respond to and destroy tumor cells. Thalidomide and the IMiDs’ costimulatory action on primary human T cells enhance antitumor activity mediated by the Th-1 cytokines IL-2 and IFN-γ. The costimulation is thought to overcome the T cell unresponsiveness and prevent the release of suppressive factors, thereby enabling tumor-specific cells to kill tumor cells. Thalidomide and the IMiDs are also thought to costimulate macrophages and NK cells leading to antitumor activity as discussed earlier. Anti-angiogenic and pro-apoptotic activities of thalidomide and the IMiDs are also thought to play a role in the apparent efficacy seen in various highly vascularized solid tumors through inhibition of VEGF and induction of growth arrest respectively.
FUTURE OF THALIDOMIDE AND ITS ANALOGUES
Thalidomide has re-surfaced in the field of oncology, despite its troubled history as a teratogen. The increasing realization of its potential clinical utility in different neoplasms make the study of thalidomide and its analogues very promising.It has yet to be approved for multiple myeloma. Recent reports of potential efficacy in other solid tumors have increased its experimental use and initiation of further clinical trials. The development of the IMiDs is an example of how active research efforts contribute to the synthesis of new thalidomide analogues that provide improved efficacy and/or reducing toxicity. Particulary lenalidomide has significantly higher immunomodulatory and anti-angiogenic potency then thalidomide and also has less side effects then thalidomide. These properties of IMiDsmade them potentially important therapeutics in cancer.While the IMiDs have shown encouraging results in both animal models and have successfully entered clinical trials, efforts are still underway to improve the toxicity profile as well as understanding further and identifying specific molecular targets that would also help delineate the neoplasms for which it may exhibit clinical potency.
The rehabilitation of thalidomide has increased its experimental use in numerous oncologic and inflammatory conditions and its analogues also shows a promising result in different malignancies but the exact mechanism of anti tumour activity of thalidomide is unknown. Thalidomide possesses many properties that can help us to explain its anti tumour activity but these are not so specific in explaining about targets. Therefore, despite the success of these agents in certain types of neoplasms, the specific molecular mechanisms and targets are still incompletely understood. Understanding of the precise mechanisms of action will help in the rational design of better thalidomide analogues, optimizing clinical applications, and ultimately translating into beneficial activity in specific neoplasms.
1.Tseng S, et al.(1996) Rediscovering thalidomide: a review of its mechanism of action, side effects, and potential uses. J Am Acad Dermatol ; 35 : 969-79.
2.Muller GW. Thalidomide: From tragedy to new drug discovery. Chemtech 1997 : 21-215.
3.Steven K. Teo(2005) , “Properties of Thalidomide and its Analogues: Implications for Anticancer Therapy” The AAPS Journal; 7 (1) Article 3 (http://www.aapsj.org).
4.“Thalidomide in the Treatment of Plasma Cell Malignancies”, Journal of Clinical Oncology, Vol 19, No 16 (August 15), 2001: pp 3593-3595
5.D'Amato, R. J.; Loughnan, M. S.; Flynn, E.; Folkman, J. (1994). "Thalidomide is an inhibitor of angiogenesis". Proceedings of the National Academy of Sciences of the United States of America 91 (9): 4082–4085.
6.Verheul, H. M. W.; Panigrahy, D.; Yuan, J.; d’Amato, R. J. (1999). "Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits". British Journal of Cancer 79 (1): 114–118.
8.Singhal, S.; Mehta, J.; Desikan, R.; Ayers, D.; Roberson, P.; Eddlemon, P.; Munshi, N.; Anaissie, E. et al. (1999). "Antitumor Activity of Thalidomide in Refractory Multiple Myeloma". New England Journal of Medicine 341 (21): 1565–1571.
12."FDA Approval for Thalidomide". National Cancer Institute. Retrieved 8 January 2012.
13.Anderson, K. C. (2005). "Lenalidomide and Thalidomide: Mechanisms of Action—Similarities and Differences". Seminars in Hematology 42 (4 Suppl 4): S3–S8.
14.Rao KV (September 2007). "Lenalidomide in the treatment of multiple myeloma". American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists 64 (17): 1799–807.
15.Brown, RD; Spencer A, Ho PJ, Kennedy N, Kabani K, Yang S, Sze DM, Aklilu E, Gibson J, Joshua DE (2009 Nov). "Prognostically significant cytotoxic T cell clones are stimulated after thalidomide therapy in patients with multiple myeloma". Leukemia & Lymphoma 50 (11): 1860–4.
16. Folkman J (1975), “ Tumor angiogenesis: a possible control point in tumor growth”, Ann Intern Med;82:96–100.
17. Search of: pomalidomide". Clinicaltrials.gov. Retrieved 2012-09-01.
18. Raghupathy R, Billett HH (March 2009). "Promising therapies in sickle cell disease". Cardiovasc Hematol Disord Drug Targets 9 (1): 1–8.
19.Tohnya TM, Hwang K, Lepper ER, et al.( 2004), “ Determination of CC-5013, an analogue of thalidomide, in human plasma by liquid chromatography-mass spectrometry”. J Chromatogr B Analyt Technol Biomed Life Sci; 811:135–41.
20.Raje N, Anderson KC (2002), “ Thalidomide and immunomodulatory drugs as cancer therapy”, Curr Opin Oncol; 14:635–40.
21.Dredge K, Marriott JB, Todryk SM, et al.(2002), “ Protective antitumor immunity induced by a costimulatory thalidomide analog in conjunction with whole tumor cell vaccination is mediated by increased Th1- type immunity” . J Immunol; 168:4914–9.
22.Kenyon BM, Browne F, D’Amato RJ (1997 ), “ Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization”. Exp Eye Res ; 64:971–8.
23.Wnendt S, Finkam M, Winter W, Ossig J, Raabe G, Zwingenberger K ( 1996) “Enantioselective inhibition of TNF-alpha release by thalidomide and thalidomide-analogues”. Chirality ; 8:390-6.
24. Frederickson RC, Slater IH, Dusenberry WE, Hewes CR, Jones GT, Moore RA (1977), “A comparison of thalidomide and pentobarbital - new methods for identifying novel hypnotic drugs”. J Pharmacol Exp Ther ; 203:240–51.
25.Corral LG, Haslett PA, Muller GW, et al.( 1999), “ Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha”. J Immunol; 163:380–6.
26.Davies FE, Raje N, Hideshima T, et al.(2001) , “Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma”. Blood ; 98:210–6.
27. Corral LG, Kaplan G ( 1999), “ Immunomodulation by thalidomide and thalidomide analogues”. Ann Rheum Dis ;58(Suppl 1):I107–13.
28.Marriott JB, Clarke IA, Dredge K, Muller G, Stirling D, Dalgleish AG(2002),“Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) T cells”. Clin Exp Immunol ; 130:75–84.
29.Jeanny B. Aragon-Ching, Haiqing Li, Erin R. Gardner, and William D. Figg(June 2007), “Thalidomide Analogues as Anticancer Drugs” NIH Public Access Author Manuscript ;Recent Pat Anticancer Drug Discov.; 2(2): 167–174.
30.Hideshima T, Chauhan D, Shima Y, et al.( 2000), “ Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy”. Blood;96:2943–50.
31.Mitsiades N, Mitsiades CS, Poulaki V, et al.( 2002), “Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications”. Blood; 99:4525–30.
32. Gandhi AK, Kang J, Naziruddin S, Parton A, Schafer PH, Stirling DI (2006), “Lenalidomide inhibits proliferation of Namalwa CSN.70 cells and interferes with Gab1 phosphorylation and adaptor protein complex assembly”. Leuk Res;30:849–58.
33.Richardson P, Schlossman R, Anderson K (2002), “ Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma”. Blood.;100:3063-3067.
34.Hideshima T, Chauhan D, Shima Y, et al.(2000), “Thalidomide and its analog overcome drug resistance of human multiple myeloma cells to conventional therapy”. Blood.;96:2943-2950.
35.Singhal S, Mehta J, Desikan R, et al.( 1999), “Anti-tumor activity of thalidomide in refractory multiple myeloma”. N Engl J Med ;341:1565-1571.
36.Hwu W, Krown S, Menell J, et al.(2003), “ Phase II study of temozolomide plus thalidomide for the treatment of metastatic melanoma”. J Clin Oncol ;21:3351-3356.
37. Maples W, Stevenson J, Sumrall S, Naughton M, Schwartz J(2004), “Advanced pancreatic cancer: a multi-institutional trial with gemcitabine and thalidomide”. J Clin Oncol ;22:4082.
38.Haslett P, Corral L, Albert A, Kaplan G (1998), “Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation,cytokine production, and cytotoxic responses in the CD8+ subset”. J ExpMed ;187:1885-1982.
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