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Synthesis of Bendamustine ..

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Paclitaxel is one of several cytoskeletal drugs that target tubulin

Our previous study demonstrated that SGI-1776 inhibit cap-dependent translation process mediated by decreasing of 4E-BP1 phosphorylation at Thr37/46 in MCL cells. Consistent with this finding, we observed that 5μM of SGI-1776 treatment for 24hr effectively reduced the protein synthesis (). This effect was also observed in MCL primary sample (60% decrease), and to a lesser extent in SMZL primary sample (10% reduction). These results suggest that SGI-1776 is effective in decreasing translation processes in B-cell lymphoma. With regards to effects on protein translation, bendamustine on the other hand, showed differential responses in these B-cell lymphoma models with 10%, 50% and 15% decrease in JeKo-1 cell line, MCL and SMZL primary cells, respectively (). Bendamustine is not known to inhibit protein translation directly, and hence the observed decline may be a secondary effect following disruption of global RNA synthesis or DNA damage response (, and ). This observation is intriguing and it is worth further investigation and could be used in biomarker studies. Combination treatment with SGI-1776 and bendamustine also showed differential responses in inhibition of global protein synthesis (). Heterogeneity among patient samples is a likely reason for such variable results, however, in all of these B-cell lymphoma models, especially in primary cells, combination of SGI-1776 with bendamustine leads to greater inhibition of the global protein synthesis compared to single agent treatments.

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N2 - Idelalisib is a targeted agent that potently inhibits PI3Kd which is exclusively expressed in hematological cells. Bendamustine is a well-tolerated cytotoxic alkylating agent which has been extensively used for treatment of chronic lymphocytic leukemia (CLL). Both these agents are FDA-approved for CLL. To increase the potency of idelalisib and bendamustine, we tested their combination in primary CLL lymphocytes. While each compound alone produced a moderate response, combination at several concentrations resulted in synergistic cytotoxicity. Idelalisib enhanced the bendamustine-mediated DNA damage/repair response, indicated by the phosphorylation of ATM, Chk2, and p53. Each drug alone activated γH2AX but combination treatment further increased the expression of this DNA damage marker. Compared with the control, idelalisib treatment decreased global RNA synthesis, resulting in a decline of early-response and short-lived MCL1 transcripts. In concert, there was a decline in total Mcl-1 protein in CLL lymphocytes. Isogenic mouse embryonic fibroblasts lacking MCL1 had higher sensitivity to bendamustine alone or in combination compared to MCL1 proficient cells. Collectively, these data indicate that bendamustine and idelalisib combination therapy should be investigated for treating patients with CLL.

Reductive Amination of Aldehydes and Ketones ..

Idelalisib is a targeted agent that potently inhibits PI3Kd which is exclusively expressed in hematological cells. Bendamustine is a well-tolerated cytotoxic alkylating agent which has been extensively used for treatment of chronic lymphocytic leukemia (CLL). Both these agents are FDA-approved for CLL. To increase the potency of idelalisib and bendamustine, we tested their combination in primary CLL lymphocytes. While each compound alone produced a moderate response, combination at several concentrations resulted in synergistic cytotoxicity. Idelalisib enhanced the bendamustine-mediated DNA damage/repair response, indicated by the phosphorylation of ATM, Chk2, and p53. Each drug alone activated γH2AX but combination treatment further increased the expression of this DNA damage marker. Compared with the control, idelalisib treatment decreased global RNA synthesis, resulting in a decline of early-response and short-lived MCL1 transcripts. In concert, there was a decline in total Mcl-1 protein in CLL lymphocytes. Isogenic mouse embryonic fibroblasts lacking MCL1 had higher sensitivity to bendamustine alone or in combination compared to MCL1 proficient cells. Collectively, these data indicate that bendamustine and idelalisib combination therapy should be investigated for treating patients with CLL.

AB - Idelalisib is a targeted agent that potently inhibits PI3Kd which is exclusively expressed in hematological cells. Bendamustine is a well-tolerated cytotoxic alkylating agent which has been extensively used for treatment of chronic lymphocytic leukemia (CLL). Both these agents are FDA-approved for CLL. To increase the potency of idelalisib and bendamustine, we tested their combination in primary CLL lymphocytes. While each compound alone produced a moderate response, combination at several concentrations resulted in synergistic cytotoxicity. Idelalisib enhanced the bendamustine-mediated DNA damage/repair response, indicated by the phosphorylation of ATM, Chk2, and p53. Each drug alone activated γH2AX but combination treatment further increased the expression of this DNA damage marker. Compared with the control, idelalisib treatment decreased global RNA synthesis, resulting in a decline of early-response and short-lived MCL1 transcripts. In concert, there was a decline in total Mcl-1 protein in CLL lymphocytes. Isogenic mouse embryonic fibroblasts lacking MCL1 had higher sensitivity to bendamustine alone or in combination compared to MCL1 proficient cells. Collectively, these data indicate that bendamustine and idelalisib combination therapy should be investigated for treating patients with CLL.

22/01/2014 · Original Article

Bendamustine forms organic ions that bind to other ions to induce cell death in both latent and dividing cells. The exact mechanism by which these linkages cause cell death is still unknown, however Bendamustine is known to form cross-links with , which causes breakage of strands and inhibition of DNA synthesis.

SGI-1776 is a small molecule Pim kinase inhibitor that primarily targets c-Myc-driven transcription and cap-dependent translation in mantle cell lymphoma (MCL) cells. Bendamustine is an alkylating chemotherapeutic agent approved for use in B-cell lymphoma that is known to induce DNA damage and to initiate response to repair. We hypothesized that while each drug leads to the effects as stated above, combination of these drugs will enhance SGI-1776-induced inhibition of global transcription and translation processes, while promoting bendamustine-triggered decrease of DNA synthesis and DNA damage response in B-cell lymphoma. Both SGI-1776 and bendamustine as single agents effectively induced apoptosis and when used in combination, additive effect in cell killing was observed in MCL cell lines, JeKo-1 and Mino, as well as MCL and splenic marginal zone lymphoma (a type of B-cell lymphoma) primary cells. As expected, SGI-1776 was effective in inducing decrease of global RNA and protein synthesis, while bendamustine significantly inhibited DNA synthesis and generated DNA damage response. When used in combination, effects were intensified in DNA, RNA and protein syntheses compared to single agent treatments. Together, these data provided foundation and suggested feasibility of using Pim kinase inhibitor in combination with chemotherapeutic agents such as bendamustine in B-cell lymphoma.

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  • that the butanoic acid group of the anticancer drug bendamustine ..

    Treatment with bendamustine also leads to disruption of the matrix function of DNA in DNA synthesis.

  • Bendamustine - National Institutes of Health

    Bendamustine hydrochloride 2.5 mg/ml powder for concentrate for solution for infusion - by medac GmbH

  • BENDAMUSTINE « New Drug Approvals

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03/07/2013 · Bendamustine hydrochloride was ..

Bendamustine was first synthesized in the 1960s and was extensively used in Europe. In the US, it was approved by the FDA in 2008 for use in treating CLL and non-Hodgkin’s lymphoma, many of which are B-cell diseases. Currently, clinical trials are ongoing using bendamustine in combination with rituximab–an FDA approved anti-CD20 for B-cell malignancies, to treat non-Hodgkin’s lymphoma. In B-cell lymphomas, such as MCL, high relapse rate was observed following conventional chemotherapeutic regimens such as R-CHOP. So far, clinical trials using bendamustine in combination with rituximab have shown impressive results, and a phase III trial in follicular, indolent lymphoma and MCL showed a >90% overall survival rate, and >40% complete remission, indicating that bendamustine is an effective therapeutic agent in B-cell lymphoma. Importantly, this regimen was also well-tolerated by patients.

Bendamustine in B-Cell Malignancies: The New 46-Year …

With the existing knowledge on both drugs, we hypothesize that combination of transcription and translation targeting SGI-1776 with DNA-damaging bendamustine will additively or synergistically disrupt oncogenic processes by introducing DNA damage, disrupting DNA synthesis and repair, while blocking transcription and translation processes which ultimately lead to cell death in B-cell lymphoma. We used established MCL cell lines and fresh B-cell lymphoma primary cells to examine the cellular response to such combination therapy approach, with respect to cell death, reduction of global DNA, RNA and protein synthesis levels as well as DNA damage. Our study provides the foundation and establishes the basic evaluation of the therapeutic approach using Pim kinase inhibitor in combination with bendamustine in B-cell lymphoma, which can lead to more in-depth study in the future.

Bendamustine hydrochloride Intermediates, …

All data plots were prepared and analyzed using GraphPad software (GraphPad). Cell line data were performed in triplicates and were shown as mean value ± SEM. DMSO was used as a vehicle control. Fractional analysis was used to determine if the drug combination caused less than, equal to or more than additive effect on inducing of apoptosis (). Data points fell into expected results ±20% were categorized into one of these three outcomes. Similar calculation was performed in determining SGI-1776 and bendamustine combination effect on inhibition of DNA, RNA and protein synthesis, as well as increased γ-H2AX phosphorylation in MCL cell lines and B-cell lymphoma primary samples.

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