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Thalidomide showed cyclooxygenase (COX)-1/2 inhibitory activity with a potency comparable to that of aspirin. Structural development studies of thalidomide resulted in potent COX-1/2 inhibitors, and COX-1-selective and COX-2-selective inhibitors.
Thalidomide, (1), is a known inhibitor of TNF-alpha release in LPS stimulated human PBMC. Herein we describe the TNF-alpha inhibitory activity of amino substituted analogs of thalidomide (1) and its isoindolin-1-one analog, EM-12 (2). The 4-amino substituted analogs were found to be potent inhibitors of TNF-alpha release in LPS stimulated human PBMC.
BACKGROUND: Melkersson-Rosenthal syndrome (MRS) is a rare disorder of unknown etiology characterized by a triad of symptoms: recurrent orofacial swelling, relapsing facial palsy. and a fissured tongue. A differential diagnosis must be made with other granulomatous diseases, such as sarcoidosis and oral Crohn disease; however, the histologic findings of noncaseating, sarcoidal granulomas support the diagnosis of MRS. RESULTS: Many therapeutic modalities have been described for this disease. In this case report, we present a patient with MRS that was treated with thalidomide because of the identification of tumor necrosis factor a in the lesion by immunohistochemical analysis. This is the first reported detection of tumor necrosis factor a in an MRS lesion, as well the first reported use of thalidomide to treat this clinical condition.
Thalidomide is having increasing application in the management of a wide spectrum of immunologically-mediated and infectious disorders. It is also suggested that this agent may also have be of importance in the treatment of solid and non-solid malignancies. The present article reviews the role of thalidomide in the management of malignancy and outlines its possible potential in the treatment of malignancy of the mouth.
A novel solid-phase synthesis of thalidomide and its metabolites and analogues is described. The synthetic strategy involves the coupling of hydroxymethyl polystyrene with phthalic anhydride to form the resin-linked acid. The acid is then reacted with primary amines followed by acid or base treatment to form thalidomide and its analogues with either open or closed phthalimide rings. Most of the analogues are synthesized with high yields (40.3-98.1% in three steps) and purities (92.3-98.9%).
The effect of high oxygen concentrations on lungs of neonatal rats was studied. In addition, some oxygen-exposed animals were treated with either dexamethasone or thalidomide. No gross histologic changes were noted in the lungs following exposure to 95% oxygen nor were there changes in the total number or the phenotypic distribution of BAL cells obtained from these lungs compared to lungs from air exposed (control) neonatal rats. The majority of the BAL cells were CD45+ leukocytes (macrophages). However, when BAL cells were exposed to LPS in vitro, TNF-alpha production was higher in cells from rats exposed to 95% oxygen compared to cells from rats exposed to ambient air. In addition, lung TNF-alpha and IL-6 mRNA levels were increased after exposure to 95% oxygen. In the lungs of animals treated with either dexamethasone or thalidomide, TNF-alpha mRNA levels were reduced, while only dexamethasone treatment also reduced IL-6 mRNA levels.
Exposure of primary rat glial cells, mostly astrocytes, to heat-inactivated Mycoplasma fermentans triggers the production of tumor necrosis factor alpha (TNFalpha) nitric oxide (NO) and prostaglandin E2 (PGE2). To attenuate the production of these proinflammatory mediators, four agents: aminoguanidine, pentoxifylline, thalidomide and IL-10 were added to astrocyte cultures. Aminoguanidine (1 and 3 mM), an inhibitor of inducible nitric oxide synthase (iNOS), suppressed the production of the three mediators. TNFalpha was the most sensitive to thalidomide, showing dose-response inhibition at concentrations of 20 microg/ml, 50 microg/ml and 250 microg/ml. PGE2 was affected only by concentrations of 50 microg/ml and 250 microg/ml, whereas NO responded solely to the highest amount of this inhibitor. The cytokine IL-10, at 10 U and 50 U, inhibited only TNFalpha production. Our results imply that selective suppression of proinflammatory mediators by various agents may prove feasible for amelioration of central nervous system inflammatory diseases.
Multiple myeloma (MM)--a malignancy of the bone marrow--remains incurable by current therapies, and there is an urgent need for new drugs based on a better understanding of the underlying disease biology. MM is characterized by monoclonal plasma cells that accumulate in the bone marrow, which provides a microenvironment that promotes tumor cell growth and survival and protection against various therapeutic agents. The MM cell interacts with bone marrow stromal cells and endothelial cells, as well as osteoblasts and osteoclasts. Our understanding of the tumor microenvironment has already prompted the development of new agents that are aimed at disrupting the multiple facets of these interactions. It has also enabled the development of a comprehensive and rational approach to preclinical evaluation of new agents, facilitating the translation of in vitro studies to in vivo tumor models and, subsequently, to clinical trials. In this review, we describe the preclinical studies that led to the development of clinical trials of thalidomide and its immunomodulatory derivatives as therapeutic agents for MM. These drugs, alone or in combination, have shown impressive activity at all stages of the disease, and these demonstrations of clinical benefit have in turn validated our model systems for drug discovery in MM. Integration of data from clinical trials and laboratory studies will allow the design of future clinical trials that combine thalidomide and its derivatives with other drugs, ultimately leading to more effective therapies and better outcomes in patients with MM.
We report two cases of severe leg ulcerations in patients being treated with thalidomide for graft-versus-host disease following bone marrow transplantation. Local wound care and debridement were attempted, but one patient required skin grafting to ensure healing. We propose that this complication may be due to the antiangiogenic properties of thalidomide and urge careful attention to skin breakdown in patients being treated with this compound.
We evaluate the efficacy of the oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) in 71 refractory/relapsed multiple myeloma patients, including a prognostic analysis to predict both response and survival. Patients received thalidomide at escalating doses (200-800 mg/day), daily cyclophosphamide (50 mg/day) and pulsed dexamethasone (40 mg/day, 4 days every 3 weeks). On an intention-to-treat basis and using the EBMT response criteria, 2% patients reached complete response (CR), 55% partial response (PR) and 26% minor response (MR) yielding a total response (CR+PR+MR) rate of 83% after 3 months of therapy. After 6 months of therapy, responses were maintained including a 10% CR. The 2-year progression free and overall survival were 57 and 66%, respectively. A favorable response was associated with beta2 microglobulin < or =4 mg/dl, platelets >80 x 10(9)/l and nonrefractory disease. Regarding survival, low beta2 microglobulin (< or =4 mg/dl), age (< or =65 years) and absence of extramedullary myelomatous lesion were associated with a longer survival. Major adverse effects included constipation (24%), somnolence (18%), fatigue (17%) and infection (13%). Only 7% of patients developed a thrombo-embolic event. ThaCyDex is an oral regimen that induces a high response rate and long remissions, particularly in relapsing patients with beta2 microglobulin < or =4 mg/dl and < or =65 years.
Thalidomide alone or in combination with steroids has significant activity in multiple myeloma (MM). However, given its teratogenic potential, analogs have been synthesized, retaining the anti-MM activity without these side effects. We examined the anti-MM activity of two thalidomide analogs, CPS11 and CPS49. Direct cytotoxicity of the drugs on myeloma cell lines and patient myeloma cells was examined using thymidine uptake. Tumor cell apoptosis was evaluated by flow cytometry as well as Western blotting for caspase and PARP cleavage. Cellular signaling events were examined by immunoblotting for phosphorylated proteins. Both drugs inhibit proliferation of several MM cell lines sensitive and resistant to conventional therapies. They decrease secretion of IL-6, IGF, and VEGF by marrow stromal cells. Importantly, they inhibit proliferation of MM cells adherent to stromal cells. These drugs induce caspase-mediated apoptosis in MM cell lines, as well as patient MM cells. They inhibit the PI3K/Akt and JAK/STAT (signal transducers and activators of transcription) pathways in MM cells and are antiangiogenic in matrigel-based assays. CPS11 and CPS49 have potent antimyeloma activity and can overcome protective effects of the tumor microenvironment. They have potent antiangiogenic activity and direct effect on bone marrow stroma. These encouraging preclinical data provide the basis for further evaluation in the clinic.
The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone (Thal/Dex) on disease course and bone disease in patients with refractory/relapsed myeloma who were under zoledronic acid therapy. We studied 35 patients, who received thalidomide at a dose of 200 mg/daily. We measured, pre-, 3 and 6 months post-treatment soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), osteoprotegerin (OPG), osteopontin (OPN), markers of bone resorption and formation. Before treatment, patients had increased levels of sRANKL/OPG ratio, bone resorption markers and OPN, while they had suppressed bone formation. The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease. Thal/Dex administration resulted in a significant reduction of sRANKL/OPG ratio, and bone resorption. Bone formation, OPG and OPN did not show any alteration. Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers. Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months. The response rate was 65.7%. The median survival was 19.5 months. beta2-microglobulin, type of response and International Staging System predicted for survival. These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio.
Plasma cell leukemia (PCL) is an aggressive disease with poor prognosis and a median survival of only 2-6 months. Currently, no standard therapy is available, but intensive polychemotherapy appears to be more effective than the conventional melphalan plus prednisone. However, the efficacy of thalidomide in PCL has not yet been widely evaluated. Recently, treatment with thalidomide has been reported to yield promising results in refractory multiple myeloma. Here, we report on a patient with primary PCL in whom first-line treatment with thalidomide/dexamethasone resulted in a rapid response and achievement of a very good partial remission.
We have treated 17 refractory or relapsed multiple myeloma patients resistant to chemotherapy with thalidomide at a dose of 200-800 mg/day. Eleven patients responded, five of whom had a very good partial response (> 75% decline in M protein) and another five exhibited a partial response (> 50% decline in M protein). Except for one patient, treatment was well tolerated with only mild side-effects. Thalidomide should be included in the therapeutic options for refractory myeloma.
Thirty patients with myelodysplastic syndromes (MDS) were treated with thalidomide at 100 mg/d p.o., increased as tolerated to 400 mg/d for 12 weeks. Levels of apoptosis, macrophage number, microvessel density (MVD), tumour necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), interleukin 6 (IL-6), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were determined in the serum, bone marrow (BM) plasma and BM biopsies before and after therapy. Pretherapy biological characteristics of MDS patients were compared with similar studies performed in 11 normal volunteers. Ten patients demonstrated haematological improvement in the erythroid series, six becoming transfusion independent. Responders had a higher pretherapy platelet count (P < 0.048) and lower BM blasts (P < 0.013). Median time to response was 10 weeks, and four remain in remission beyond a year. Pretherapy MDS BMs showed higher MVD (P < 0.001) and TGF-beta (P < 0.03) and higher serum TNF-alpha (P < 0.008) compared with normal control subjects. After therapy, only BM TGF-beta decreased significantly (P < 0.002). Pretherapy haemoglobin was directly related to serum VEGF (P < 0.001) in responders and inversely related in non-responders (P < 0.05), suggesting the possibility that angiogenesis may be a primary pathology in the former and a consequence of anaemia-induced hypoxia in the latter. We conclude that thalidomide has important clinical and biological effects in at least a subset of MDS patients, but the precise mechanism of its action remains unknown and requires further study including a larger number of patients.
Mantle cell lymphoma is an aggressive B-cell lymphoma with a poor median survival despite conventional therapy. Here, we present the case of a patient with multiply relapsed mantle cell lymphoma, having failed treatment with chemotherapy, steroids and rituximab. He was treated with single-agent thalidomide at a dose of 800 mg daily and entered a good partial remission which was maintained for the next 6 months. There is clearly a need for further studies of thalidomide in mantle cell lymphoma to confirm this promising initial result.
Between November 1998 and April 2000, the combination of thalidomide and dexamethasone was evaluated in 47 consecutive patients with multiple myeloma that was resistant to prior high-dose dexamethasone-based therapies. Remission was observed in 22 patients (47%), including six patients with complete remission. Side-effects were frequent, mild and usually reversible, but deep vein thrombosis occurred in 8% of patients. Survival and remission times were longer among patients treated for previous resistant disease rather than for resistant relapse. This experience supports the use of thalidomide-dexamethasone in myeloma patients with resistant disease and justifies further trials in newly diagnosed patients.
BACKGROUND: Low-dose thalidomide therapy (median dose 100 mg/day, 50-200 mg/day) in chronic discoid lupus erythematosus was studied with regard to efficacy, tolerance, and toxicity in 22 patients. Intense contraceptive precautions were taken in women patients of childbearing age. METHODS: An open uncontrolled trial was conducted. Age, the total drug intake, disease duration, extent/severity, and adverse reactions were studied with regard to the final clinical outcome. The follow-up duration was 1.8 years (range 1 month to 3 years). RESULTS: With the exception of age (inverse correlation, P < 0.01), the parameters studied did not influence the final clinical amelioration: complete responders numbered 54.5%, partial responders 22.7%, and 13.6% were withdrawn from the trial with complaints of intolerance. The initial (first month) clinical response correlated significantly with the final one (P < 0.01). Drowsiness (40.9%) and somnolence (18.2%) were the most common side-effects, without affecting seriously the daily life of the participants. No case of real neurotoxicity was confirmed. Relapses occurred within 39.4 +/- 21.4 days after drug withdrawal, presenting a milder clinical picture. CONCLUSIONS: In the context of a predictable final outcome, low-dose thalidomide therapy is effective as an alternative choice in cases resistant to the usual treatment.