Design and biological characterization of hybrid compounds of curcumin and thalidomide for multiple myeloma
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Abstract:
In our efforts to develop effective treatment agents for human multiple myeloma (MM), a series of hybrid molecules based on the structures of thalidomide (1) and curcumin (2) were designed, synthesized, and biologically characterized in human multiple myeloma MM1S, RPMI8226, U266 cells, and human lung cancer A549 cells. The biological results showed that two hybrid compounds, 5 and 7, exhibited significantly improved lethal effects towards all three human MM cell models compared to 1 or 2 alone, as well as the combination of 1 and 2. Furthermore, mechanistic studies in U266 cells demonstrated that 5 and 7 can induce the production of reactive oxygen species (ROS) and cause G1/S arrest, thus leading to apoptosis and cell death. Additionally, they exhibited inhibitory effects on NFκB activation in A549 cells. Collectively, the results obtained from these hybrid compounds strongly encourage their further optimization as new leads to develop effective treatment agents for human MM.Keywords:
Human lung
Objective To assess the effectiveness and safety of thalidomide for treating multiple myeloma.Methods Randomized controlled trials(RCTs) of thalidomide for multiple myeloma were collected from CHKD Data Library(1994-2010),Wanfang Medical Journals(1994-2010).The methodological qualities of the included studies were evaluated,and data analyses were performed using the Cochrane Collaboration's software RevMan 4.3.Results A total of 7 RCTs involving 193 patients were included.As for total effective rate and the effectiveness of reducing M-protein and reducing myeloma cells amounts,improving anaemia complete remission rate,significant differences were found between with or without thalidomide for the treatment of multiple myeloma(OR=3.54,95%CI=1.83-6.81;OR=3.19,95%CI=1.75-5.82;OR=3.07,95%CI=1.67-5.67;OR=2.96,95%CI=1.58-5.54).Conclusion According to the domestic evidence,treatment for multiple myeloma with thalidomide can improve the total effectiveness.However,more high–quality,large-sample,randomized,double-blind,controlled trials are required.
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Refractory (planetary science)
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Refractory (planetary science)
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The field of multiple myeloma therapeutics has been an active one for many years, but perhaps no more so than in the past decade. The introduction of thalidomide, lenalidomide and bortezomib in the treatment of this disease highlights clinical advances made during this period. While these agents were initially utilized in the setting of relapsed and refactory disease, they are now part of the therapeutic armamentarium for transplant-eligible and transplant-ineligible patients with newly diagnosed multiple myeloma. The principles of management applied in the care of newly diagnosed multiple myeloma are reviewed in this article, along with the clinical studies supporting the use of thalidomide, lenalidomide and bortezomib in newly diagnosed multiple myeloma. Management of treatment-related side effects is also discussed, since it constitutes a critical element in the successful management of patients with this disease. Combination regimens utilizing thalidomide, lenalidomide and bortezomib are also highlighted, as these regimens are likely to play an increasingly important role in myeloma therapy in the future.
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Early anticancer research involving thalidomide was abandoned in the 1960s as the catastrophe surrounding the drug emerged, but research efforts were picked up in the 1990s when thalidomide’s antiangiogenic and anti-tumour necrosis factor properties were explored. More than 50,000 patients with multiple myeloma are estimated to have been treated with thalidomide to date. Research with thalidomide provides clear and convincing evidence that thalidomide monotherapy is efficacious in relapsed and refractory patients with multiple myeloma. Results typically show a consistent 30% (95% confidence interval 27–32%) response rate (partial response + complete response, defined as a reduction of at least 50% in the monoclonal protein). Thalidomide treatment compares favourably with other typical treatments for multiple myeloma. In seven trials that included 332 patients, vincristine, adriamycin and dexamethasone (VAD) had a response rate of 39% (32–45%), while a trial in 193 patients showed a response rate with bortezomib of 27% (21–34%). The use of thalidomide in combination therapy could boost its efficacy further. More studies to look at the toxicity of the drug need to be carried out. Despite thalidomide’s dark past, this drug is of major interest and could be brought back to clinical use in a controlled manner.
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Thalidomide given at relatively low, tolerable doses reduces tumour burden in patients with relapsing or progressing multiple myeloma, according to results presented at the International Myeloma Workshop last week (Sept 1-5, Stockholm, Sweden). “Nothing untoward happened in the way of side effects”, says lead investigator Brian Durie (Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA, USA). “Thalidomide is working well enough now for us to think about using it as a first or second-line treatment”, rather than as a last resort.
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Autologous stem-cell transplantation
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Objective: To discuss the clinical efficacy of the Thalidomide combined with MP and VAD in the patients with multiple myeloma. Methods: Clinic data of 42 patients with multiple myeloma used Thalidomide combined with MP and VAD were analyzed retrospectively. Results: 32 with multiple myeloma in first-time treatment group were given Thalidomide combined with MP, the total effective rate was 81.2%; 10 cases with multiple myeloma in relapse group were given Thalidomide combined with VAD, the total effective rate was 80.0%. Conclusion: Thalidomide combined with MP and VAD in the treatment of multiple myeloma were better than that of conventional therapy scheme (MP or VAD), and less side effects, good tolerance of patients or certain efficacy.
Clinical efficacy
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Cutaneous involvement has been reported in all types of malignant plasma cell disorders including multiple myeloma, solitary myeloma of bone, plasma cell leukemia, and extramedullary plasmacytoma. But metastatic plasmacytomas in the skin are rare in multiple myeloma and extramedullary plasmacytoma. If skin tumors appear during the course of multiple myeloma, these should be interpreted as a sign of poor prognosis. Treatment of patients with resistant multiple myeloma is challenging. Thalidomide has recently shown antitumor activity in patients with refractory myeloma. Until the introduction of thalidomide, no drugs other than cytotoxic agents and glucocorticoids had shown antitumor activity to cutaneous plasmacytoma.We recently performed a clinicopathologic study of a patient with cutaneous involvement of multiple myeloma and reported our result with thalidomide therapy in this patient.
Plasma cell leukemia
Plasma cell neoplasm
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