A Mini-Review on Thalidomide: Chemistry, Mechanisms of Action, Therapeutic Potential and Anti-Angiogenic Properties in Multiple Myeloma.

Thalidomide is a drug with interesting therapeutic properties but also with severe side effects which require a careful and monitored use. Potential immunomodulatory, antiinflammatory, anti-angiogenic and sedative properties make thalidomide a good candidate for the treatment of several diseases such as multiple myeloma. Through an increase in the degradation of TNFα-mRNA, thalidomide reduces the production of TNFα by monocytes and macrophages stimulated by lipopolysaccharide or by T lymphocytes induced by mitogenic stimuli. The decreased level of TNFα alters the mechanisms of intracellular transduction by preventing the activation of NF-kB and by decreasing the synthesis of proteins, in particular IL-6, involved in cell proliferation, inflammation, angiogenesis and protection from apoptosis. Furthermore, thalidomide affects VEGF levels by down-regulating its expression. Nowadays, new safer and less toxic drugs, analogs of thalidomide, are emerging as beneficial for a more targeted treatment of multiple myeloma and several other diseases such as Crohn';s disease, rheumatoid arthritis, sarcoidosis, erythema nodosum leprosum, graft-versus-host disease.

In vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems.

Thalidomide, a drug known for its teratogenic side-effects, is used successfully to treat a variety of clinical conditions including leprosy and multiple myeloma. Intense efforts are underway to synthesize and identify safer, clinically relevant analogs. Here, we conduct a preliminary in vivo screen of a library of new thalidomide analogs to determine which agents demonstrate activity, and describe a cohort of compounds with anti-angiogenic properties, anti-inflammatory properties and some compounds which exhibited both. The combination of the in vivo zebrafish and chicken embryo model systems allows for the accelerated discovery of new, potential therapies for cancerous and inflammatory conditions.

Pomalidomide is nonteratogenic in chicken and zebrafish embryos and nonneurotoxic in vitro.

Thalidomide and its analog, Lenalidomide, are in current use clinically for treatment of multiple myeloma, complications of leprosy and cancers. An additional analog, Pomalidomide, has recently been licensed for treatment of multiple myeloma, and is purported to be clinically more potent than either Thalidomide or Lenalidomide. Using a combination of zebrafish and chicken embryos together with in vitro assays we have determined the relative anti-inflammatory activity of each compound. We demonstrate that in vivo embryonic assays Pomalidomide is a significantly more potent anti-inflammatory agent than either Thalidomide or Lenalidomide. We tested the effect of Pomalidomide and Lenalidomide on angiogenesis, teratogenesis, and neurite outgrowth, known detrimental effects of Thalidomide. We found that Pomalidomide, displays a high degree of cell specificity, and has no detectable teratogenic, antiangiogenic or neurotoxic effects at potent anti-inflammatory concentrations. This is in marked contrast to Thalidomide and Lenalidomide, which had detrimental effects on blood vessels, nerves, and embryonic development at anti-inflammatory concentrations. This work has implications for Pomalidomide as a treatment for conditions Thalidomide and Lenalidomide treat currently.

Rifampicin inhibits the retinal neovascularization in vitro and in vivo.

Rifampicin, an antibacterial drug widely used in the treatment of tuberculosis and leprosy, has recently been reported to have anti-oxidative and anti-apoptotic effects. However, its anti-angiogenic effect has not been investigated. We examined its anti-angiogenic effect on tube formation and proliferation by human umbilical vein endothelial cells (HUVECs) in vitro and on retinal neovascularization in a murine oxygen-induced retinopathy model in vivo. In addition, we explored the potential mechanisms for its anti-angiogenic effect. Rifampicin significantly suppressed HUVEC tube formation and proliferation, and its effects appeared to be mediated at least in part through inhibition of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. Retinal neovasuclarization was induced in neonatal mice by returning the retina to normoxia (21% O2) after exposure to hyperoxia (75% O2) from postnatal day 7 (P7) to P12. Rifampicin was given subcutaneously at 20mg/kg once a day from immediately after hyperoxia (P12) to P16. At P17, flat-mounted retinas were prepared and evaluated for pathological and physiological angiogenesis. Rifampicin significantly suppressed retinal neovascularization (versus vehicle treatment), but revascularization of the capillary-free area did not differ between vehicle and rifampicin treatment. Rifampicin has anti-angiogenic effects in vitro and in vivo, and may be useful as an anti-angiogenic agent in the treatment of retinal neovascularization diseases.

[An old drug as a carcinostatic. The new career of thalidomide]. / Ein altes Schlafmittel als Cancerostatikum: Die neue Karriere des Thalidomids.

Thalidomid hat eine wechselhafte Geschichte; anfangs als Schlafmittel wegen seiner teratogenen Wirksamkeit verpönt, hat es in der Behandlung des Erythema nodosum leprosum schon seit fast zehn Jahren seinen festen Platz. In den beiden letzten Jahren konnte in Klinischen Studien seine Bedeutung in der Therapie des Multiplen Myeloms und des Myelodysplastischen Syndroms nachgewiesen werden. Eines ist geblieben: Auf Grund der Teratogenität ist eine Schwangerschaft eine absolute Kontraindikation.

Thalidomide analogs from diamines: Synthesis and evaluation as inhibitors of TNF-alpha production.

Fourteen thalidomide analogs bearing two phthalimido units were prepared in high yields (83-94%) by condensation of different diamines with phthalic or 3-nitrophthalic anhydride. An in vitro investigation of the compounds as inhibitors of the TNF-alpha production was performed. The inhibition was higher for compounds bearing amino and nitro groups and was modulated by increasing the size of the spacers between the phthalimide groups.

[The revival of thalidomide: an old drug with new indications]. / Le renouveau du thalidomide. Un vieux médicament aux nouvelles indications.

Thalidomide has several mechanisms of action: several immuno-modulatory properties, an anti-angiogenic action and a hypnosedative effect. Thalidomide has been used in several cutaneous inflammatory disorders (such as erythema nodosum leprosum in lepromatous leprosy, cutaneous lupus erythematosus, severe aphtosis), cancers (relapsed/refractory multiple myeloma) and inflammatory conditions. Several side effects are associated with thalidomide; some are major: teratogenicity, peripheral neuropathy and deep venous thrombosis; some are minor, such as somnolence or abdominal pain and endocrinologic disturbances. Use of thalidomide is strictly controlled with close adherence to a birth control program and close monitoring for early development of peripheral neuropathy.

Properties of thalidomide and its analogues: implications for anticancer therapy.

Thalidomide and its immunomodulatory (IMiDs) analogs (lenalidomide, Revlimid, CC-5013; CC-4047, ACTIMID) are a novel class of compounds with numerous effects on the body's immune system, some of which are thought to mediate the anticancer and anti-inflammatory results observed in humans. Thalidomide is currently being used experimentally to treat various cancers and inflammatory diseases. It is approved for the treatment of dermal reaction from leprosy and is currently in phase III trials for multiple myeloma. Thalidomide and IMiDs inhibit the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukins (IL) 1beta, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). They also costimulate primary human T lymphocytes inducing their proliferation, cytokine production, and cytotoxic activity thereby increasing the T cells' anticancer activity. They induce an IL-2-mediated primary T cell proliferation with a concomitant increase in IFN-gamma production and decrease the density of TNF-alpha-induced cell surface adhesion molecules ICAM-1, VCAM-1, and E-selectin on human umbilical vein endothelial cells. Thalidomide stimulates the Th-1 response increasing IFN-gamma levels while CC-4047 increased IL-2 as well. Some of the above immunomodulatory activities along with anti-angiogenic, anti-proliferative, and pro-apoptotic properties are thought to mediate the IMiDs' antitumor responses observed in relapsed and refractory multiple myeloma and some solid tumor cancers. This has led to their use in various oncology clinical trials. The second generation IMiD, lenalidomide, has shown potential in treating the bone marrow disorders myelodysplastic syndrome and multiple myeloma. It is currently in phase II and III trials for these diseases respectively with numerous phase II trials in other hematologic and solid tumors.

Talidomida: una visión nueva de un tóxico antiguo / Thalidomide: a new view of an old toxic

Desde que a principios de los años 60 la talidomida fuera retirada del mercadodebido a su acción teratogénica, este fármaco ha sido ampliamente estudiado,encontrándose en él propiedades terapéuticas que han despertado nuevamente elinterés por esta molécula. Recientemente, la FDA ha aprobado su empleo en eltratamiento de ENL (Erythema Nodosum Leprosum), una manifestación aguda dela lepra. Además, actualmente se encuentra en ensayos clínicos (fase II/III) enmieloma múltiple, cáncer de mama, próstata, riñón y pulmón, mostrando buenosresultados. En este artículo se ofrece una visión general de las propiedades de latalidomida, haciendo especial hincapié en su acción inhibitoria de la angiogénesis,que podría ser responsable, al menos en parte, de su actividad antineoplásica yteratogénica

Since the early 60s, when thalidomide was withdrawn from markets, this drug ;;has been widely studied due to its teratogenic activity. The finding of new therapeutic properties has raised a new interest in this molecule, and recently the FDA ;;has approved its use in the treatment of ENL (Erythema Nodosum Leprosum), an ;;acute manifestationof leprae. Besides, thalidomide is nowadays going through clinical ;;assays (PhaseII/III) in multiple myeloma, breast, prostate, kidney and lung ;;tumours, showing good results. This article offers an overview of thalidomide ;;properties focusing on its inhibition of angiogenesis, which would be responsible, ;;at least partially, of its antineoplastic and teratogenic activity

Thalidomide derived immunomodulatory drugs (IMiDs) as potential therapeutic agents.

Thalidomide is known to be effective in the treatment of a number of conditions, including leprosy and various cancers. The exact mechanisms of action remain unclear although these are known to include anti-tumour necrosis factor (TNF)-alpha, T cell costimulatory, anti-angiogenic and anti-tumour activities. However, thalidomide is being superceded by novel structural derivatives which have been designed to have improved immunomodulatory activity and side effect profiles. These are currently being characterised and some are entering the clinic in phase I/II studies. One novel group of structural analogues are classified as the Immunomodulatory Drugs (IMiDs). This review describes the emerging immunological, anti-angiogenic and direct anti-tumour properties of thalidomide and the characterisation and clinical application of its IMiD analogues. We describe the laboratory studies which have led to the characterisation and development of IMiDs into potentially clinically relevant drugs. Early trial data suggests that these compounds may themselves become established therapies, particularly in certain cancers. Furthermore, ongoing studies will determine how best to apply these compounds to the appropriate clinical settings. We will describe the various clinical studies of lead compounds that are in progress and speculate as to the potential and future development of these exciting compounds.

Immunological effects of thalidomide and its chemical and functional analogs.

Thalidomide has recently shown considerable promise in the treatment of a number of conditions, such as leprosy and cancer. Its effectiveness in the clinic has been ascribed to wide-ranging properties, including anti-TNF-alpha, T-cell costimulatory and antiangiogenic activity. Novel compounds with improved immunomodulatory activity and side effect profiles are also being evaluated. These include selective cytokine inhibitory drugs (SelCIDs), with greatly improved TNF-alpha inhibitory activity, and immunomodulatory drugs (IMiDs) that are structural analogs of thalidomide, with improved properties. A third group recently identified within the SelCID group, with phosphodiesterase type 4-independent activity, is in the process of being characterized in laboratory studies. This review describes the emerging immunological properties of thalidomide, from a historical context to present-day clinical applications, most notably in multiple myeloma but also in other cancers, inflammatory disease, and HIV. We also describe the laboratory studies that have led to the characterization and development of SelCIDs and IMiDs into potentially clinically relevant drugs. Early trial data suggest that these novel immunomodulatory compounds may supercede thalidomide to become established therapies, particularly in certain cancers. Further evidence is required, however, to correlate the clinical efficacy of these compounds with their known immunomodulatory, antiangiogenic, and antitumor properties.

Thalidomide: an antineoplastic agent.

It has been more than three decades since the withdrawal of thalidomide from the marketplace. Thalidomide is attracting growing interest because of its reported immunomodulatory and anti-inflammatory properties. Current evidence indicates that thalidomide reduces the activity of the inflammatory cytokine tumor necrosis factor-alpha by accelerating the degradation of its messenger RNA. Thalidomide inhibits angiogenesis. Recently, thalidomide was approved for sale in the United States for the treatment of erythema nodosum leprosum, an inflammatory complication of Hansen's disease. Thalidomide has been used successfully in several other dermatologic disorders, including aphthous stomatitis, Behcet's syndrome, chronic cutaneous systemic lupus erythematosus, and graft-versus-host disease, the apparent shared characteristic of which is immune dysregulation. Many recent studies have evaluated thalidomide in patients with HIV infection, in which this drug is an efficacious agent against oral aphthous ulcers, HIV-associated wasting syndrome, HIV-related diarrhea, and Kaposi's sarcoma. Only in the last several years has thalidomide been aggressively investigated for its antiangiogenic potential and immunomodulatory properties in various tumor types. Current research on thalidomide in oncology covers investigation in a wide range of both solid tumors and hematologic malignancies.

Immunological effects of thalidomide and its chemical and functional analogs

Thalidomide has recently shown considerable promise in the treatment of a number of conditions, such as leprosy and cancer. Its effectiveness in the clinic has been ascribed to wide-ranging properties, including anti-TNF-alpha, T-cell costimulatory and antiangiogenic activity. Novel compounds with improved immunomodulatory activity and side effect profiles are also being evaluated. These include selective cytokine inhibitory drugs (SelCIDs), with greatly improved TNF-alpha inhibitory activity, and immunomodulatory drugs (IMiDs) that are structural analogs of thalidomide, with improved properties. A third group recently identified within the SelCID group, with phosphodiesterase type 4-independent activity, is in the process of being characterized in laboratory studies. This review describes the emerging immunological properties of thalidomide, from a historical context to present-day clinical applications, most notably in multiple myeloma but also in other cancers, inflammatory disease, and HIV. We also describe the laboratory studies that have led to the characterization and development of SelCIDs and IMiDs into potentially clinically relevant drugs. Early trial data suggest that these novel immunomodulatory compounds may supercede thalidomide to become established therapies, particularly in certain cancers. Further evidence is required, however, to correlate the clinical efficacy of these compounds with their known immunomodulatory, antiangiogenic, and antitumor properties.

Thalidomide: a novel template for anticancer drugs.

Thalidomide is an immunomodulatory agent that is approved for use in patients with cutaneous manifestations of erythema nodosum leprosum (ENL). It is currently under clinical investigation in a wide range of malignancies and immunologic-based disorders. Structural analogs of thalidomide have been synthesized in order to explore potential molecular targets of thalidomide, as well as to identify new therapeutics. Members of one class of analogs, termed immunomodulatory drugs (IMiD), are 100 to 1,000 times more potent than thalidomide in regulating cytokine production by peripheral blood mononuclear cells and providing a costimulatory signal for T-cell proliferation. Notably, the nature of the stimulus and the cell type are important determinants as to whether the IMiDs or thalidomide cause an inhibitory or stimulatory effect. The IMiD CDC-501 has been selected for clinical development; it had been safely administered to volunteers in single doses of 50 to 400 mg and in multiple doses of 100 mg for 7 days. Phase I/II studies of CDC-501 in multiple myeloma are in progress.

Thalidomide: current and potential clinical applications.

More than three decades after its withdrawal from the world marketplace, thalidomide is attracting growing interest because of its reported immunomodulatory and anti-inflammatory properties. Current evidence indicates that thalidomide reduces the activity of the inflammatory cytokine tumor necrosis factor (TNF)-alpha by accelerating the degradation of its messenger RNA. Thalidomide also inhibits angiogenesis. Recently, the drug was approved for sale in the United States for the treatment of erythema nodosum leprosum, an inflammatory complication of Hansen's disease. However, it has long been used successfully in several other dermatologic disorders, including aphthous stomatitis, Behçet's syndrome, chronic cutaneous systemic lupus erythematosus, and graft-versus-host disease, the apparent shared characteristic of which is immune dysregulation. Many recent studies have evaluated thalidomide in patients with human immunodeficiency virus (HIV) infection; the drug is efficacious against oral aphthous ulcers, HIV-associated wasting syndrome, HIV-related diarrhea, and Kaposi's sarcoma. To prevent teratogenicity, a comprehensive program has been established to control access to the drug, including registration of prescribing physicians, dispensing pharmacies, and patients; mandatory informed consent and education procedures; and limitation of the quantity of drug dispensed. Clinical and, in some patients, electrophysiologic monitoring for peripheral neuropathy is indicated with thalidomide therapy. Other adverse effects include sedation and constipation. With appropriate safeguards, thalidomide may benefit patients with a broad variety of disorders for which existing treatments are inadequate.