Thalidomide as a novel therapeutic agent: new uses for an old product.

Thalidomide and its immunomodulatory analogues have numerous effects on the body's immune system, including potential anti-cancer and anti-inflammatory activities. Thalidomide is currently used experimentally to treat various cancers, dermatological, neurological and inflammatory diseases. This drug is approved in the USA for cutaneous manifestations of lepromatous leprosy and is in Phase III trials for multiple myeloma. Thalidomide and its analogues modulate the immune system in various ways. Some of these immunomodulatory activities, together with the anti-angiogenic, anti-proliferative and pro-apoptotic properties, are believed to mediate anti-tumor responses as observed in multiple myeloma and some solid tumors. The analogue lenalidomide has shown potential in treating the bone marrow disorders multiple myeloma and myelodysplastic syndrome, and is presently in Phase II and III trials, respectively.

[1]  A. Baldwin,et al.  Synergistic activation of NF-kappaB by tumor necrosis factor alpha and gamma interferon via enhanced I kappaB alpha degradation and de novo I kappaBbeta degradation , 1997, Molecular and cellular biology.

[2]  R. Schwartzman,et al.  Reflex sympathetic dystrophy , 2002, Current rheumatology reports.

[3]  A. Dalgleish,et al.  Protective Antitumor Immunity Induced by a Costimulatory Thalidomide Analog in Conjunction with Whole Tumor Cell Vaccination Is Mediated by Increased Th1-Type Immunity1 , 2002, The Journal of Immunology.

[4]  L. Corral,et al.  Immunomodulation by thalidomide and thalidomide analogues , 1999, Annals of the rheumatic diseases.

[5]  R. Amato,et al.  Phase II study of CC-4047 in patients with metastatic hormone-refractory prostate cancer (HRPCa). , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  J. Zeldis,et al.  Thalidomide in the treatment of leprosy. , 2002, Microbes and infection.

[7]  M. Boccadoro,et al.  Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma. , 2004, The hematology journal : the official journal of the European Haematology Association.

[8]  A. Chott,et al.  Durable remissions after rituximab plus thalidomide for relapsed/refractory mantle cell lymphoma. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Angus G. Dalgleish,et al.  The evolution of thalidomide and its IMiD derivatives as anticancer agents , 2004, Nature Reviews Cancer.

[10]  G. Kaplan,et al.  Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation , 1993, The Journal of experimental medicine.

[11]  Sante Tura,et al.  First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma. , 2004, Haematologica.

[12]  Gilla Kaplan,et al.  Selection of Novel Analogs of Thalidomide with Enhanced Tumor Necrosis Factor α Inhibitory Activity , 1996, Molecular medicine.

[13]  G Muller,et al.  Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. , 2000, Blood.

[14]  A. Baldwin.  Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. , 2001, The Journal of clinical investigation.

[15]  P. Venugopal,et al.  Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. , 2001, Blood.

[16]  R. Schwartzman,et al.  Thalidomide has activity in treating complex regional pain syndrome. , 2003, Archives of internal medicine.

[17]  Trent D. Stephens,et al.  Dark Remedy: The Impact of Thalidomide and Its Revival as a Vital Medicine , 2000 .

[18]  Richard LeBlanc,et al.  Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. , 2002, Blood.

[19]  P. Haslett,et al.  Thalidomide Costimulates Primary Human T Lymphocytes, Preferentially Inducing Proliferation, Cytokine Production, and Cytotoxic Responses in the CD8+ Subset , 1998, The Journal of experimental medicine.

[20]  A. Dalgleish,et al.  Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects , 2002, British Journal of Cancer.

[21]  C M Lockwood,et al.  The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1 cytokine production in mitogen‐ and antigen‐stimulated human peripheral blood mononuclear cell cultures , 1995, Clinical and experimental immunology.

[22]  R. E. Staples,et al.  Assessment of the effectiveness of animal developmental toxicity testing for human safety. , 1993, Reproductive toxicology.

[23]  N. Munshi,et al.  Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. , 2002, Blood.

[24]  G. Mellin,et al.  The saga of thalidomide. Neuropathy to embryopathy, with case reports of congenital anomalies. , 1962, The New England journal of medicine.

[25]  A. Cooper,et al.  Thalidomide in dermatology , 2002, The Australasian journal of dermatology.

[26]  Shaji K. Kumar,et al.  Thalidomid: current role in the treatment of non-plasma cell malignancies. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  D. Stirling.  Thalidomide and its impact in dermatology. , 1998, Seminars in cutaneous medicine and surgery.

[28]  S. Rajkumar,et al.  Complete resolution of reflex sympathetic dystrophy with thalidomide treatment. , 2001, Archives of internal medicine.

[29]  S. Handt,et al.  Thalidomide selectively modulates the density of cell surface molecules involved in the adhesion cascade. , 1996, Immunopharmacology.

[30]  A. Fleischer,et al.  Low-dose thalidomide therapy for refractory cutaneous lesions of lupus erythematosus. , 2003, Archives of dermatology.

[31]  T. Dassopoulos,et al.  Thalidomide treatment for refractory Crohn's disease: a review of the history, pharmacological mechanisms and clinical literature , 2001, Annals of medicine.

[32]  M. Ranson,et al.  Randomized phase II study of temozolomide given every 8 hours or daily with either interferon alfa-2b or thalidomide in metastatic malignant melanoma. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  F. Kelsey.  Thalidomide update: regulatory aspects. , 1988, Teratology.

[34]  R. Amato.  Thalidomide therapy for renal cell carcinoma. , 2003, Critical reviews in oncology/hematology.

[35]  S. Kollias,et al.  Combined Thalidomide and Temozolomide Treatment in Patients with Glioblastoma Multiforme , 2004, Journal of Neuro-Oncology.

[36]  S. Rajkumar,et al.  Management of thalidomide toxicity. , 2003, The journal of supportive oncology.

[37]  M. Mayo,et al.  The transcription factor NF-kappaB: control of oncogenesis and cancer therapy resistance. , 2000, Biochimica et biophysica acta.

[38]  J. Cavenagh,et al.  An UK myeloma forum phase II study of thalidomide; long term follow-up and recommendations for treatment. , 2003, Leukemia research.

[39]  Judah Folkman,et al.  Thalidomide is an inhibitor of angiogenesis. , 1994 .

[40]  Lei Wu,et al.  Immunomodulatory drugs inhibit expression of cyclooxygenase-2 from TNF-alpha, IL-1beta, and LPS-stimulated human PBMC in a partially IL-10-dependent manner. , 2004, Cellular immunology.

[41]  G. Kaplan,et al.  Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes , 1991, The Journal of experimental medicine.

[42]  E. Maher,et al.  Phase II trial of thalidomide and carmustine for patients with recurrent high-grade gliomas. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  P. Haslett,et al.  Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. , 1999, Journal of immunology.

[44]  J. Zeldis,et al.  S.T.E.P.S.: a comprehensive program for controlling and monitoring access to thalidomide. , 1999, Clinical therapeutics.

[45]  B. Barlogie,et al.  Antitumor activity of thalidomide in refractory multiple myeloma. , 1999, The New England journal of medicine.

[46]  Gilla Kaplan,et al.  Amino-substituted thalidomide analogs: Potent inhibitors of TNF-α production , 1999 .

[47]  J R Gillette,et al.  A comparison of the teratogenic activity of thalidomide in rabbits and rats. , 1968, The Journal of pharmacology and experimental therapeutics.

[48]  A. Barrett.  Myelodysplastic syndrome--an example of misguided immune surveillance? , 2004, Leukemia research.

[49]  N. Raje,et al.  Thalidomide and immunomodulatory drugs as cancer therapy. , 2002, Current opinion in oncology.

[50]  J SHESKIN,et al.  Thalidomide in the treatment of lepra reactions , 1965, Clinical pharmacology and therapeutics.

[51]  G. Wolbring,et al.  Enhancement of Cytokine Production and AP-1 Transcriptional Activity in T Cells by Thalidomide-Related Immunomodulatory Drugs , 2003, Journal of Pharmacology and Experimental Therapeutics.

[52]  G. Macpherson,et al.  Current status of thalidomide and its role in the treatment of metastatic prostate cancer. , 2003, Critical reviews in oncology/hematology.

[53]  S. Steinberg,et al.  Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[54]  J. Menell,et al.  Phase II study of temozolomide plus thalidomide for the treatment of metastatic melanoma. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  M. Dimopoulos,et al.  Treatment of plasma cell dyscrasias with thalidomide and its derivatives. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[56]  S. Oliver.  The Th1/Th2 paradigm in the pathogenesis of scleroderma, and its modulation by thalidomide , 2000, Current rheumatology reports.

[57]  P. Richardson,et al.  Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications , 2001, Leukemia.

[58]  N. Munshi.  Recent advances in the management of multiple myeloma. , 2004, Seminars in hematology.

[59]  C. Y. Wang,et al.  NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. , 1998, Science.

[60]  G. Morgan,et al.  Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. , 2001, Blood.

[61]  T. van der Poll,et al.  A Single Oral Dose of Thalidomide Enhances the Capacity of Lymphocytes to Secrete Gamma Interferon in Healthy Humans , 2000, Antimicrobial Agents and Chemotherapy.

[62]  Chris Albanese,et al.  NF-κB Controls Cell Growth and Differentiation through Transcriptional Regulation of Cyclin D1 , 1999, Molecular and Cellular Biology.

[63]  A. Baldwin,et al.  Inhibition of NF-κB Activity by Thalidomide through Suppression of IκB Kinase Activity* , 2001, The Journal of Biological Chemistry.