Aggressive B-cell and T-cell lymphoma drug targeting treatment
With the understanding of lymphoma growth and signal transduction pathway mechanism has been provided for the development of new drugs and the number of targets. Treatment of DLBCL drug currently under clinical study include: immunomodulatory agents, histone deacetylase inhibitors, kinase inhibitors, mTOR inhibitors, and drug targeting apoptotic pathway.
Thalidomide and its derivatives represent a class of anti-inflammatory, anti-angiogenic and immunomodulatory properties of anticancer drugs. Targeting tumor cells by direct cytotoxicity and indirect interference tumor microenvironment. The anti-tumor activity of its parent compound thalidomide analogues fairly even stronger, but neurotoxicity smaller. These analogues including multiple myeloma and bone marrow dysplasia syndrome effectively lenalidomide, pomalidomide and actimid. Based on in vitro data, it seems able to see that in addition to inhibition of regulatory T cells, effector T cells Total stimulation and activation of natural killer cells other than the anti-proliferative effects and cell factor (tumor necrosis factor a, interleukin-6, interleukin-8, vascular endothelial growth factor) cut is the most important for the survival and growth of hematological malignancies. Class of immunomodulatory drugs that inhibit angiogenesis and by inhibiting the AKT pathway and enhance the expression of the P21 tumor suppressor genes play a direct anti-tumor proliferation. These in vitro experiments, however, not yet been confirmed by in vivo experiments. Taking into account the complex interactions in vivo immunoregulatory cytokines, and many of the in vitro experiment has not yet been elaborated. In phase II trials, to lenalidomide for relapsed or refractory DLBCL effective rate of 20% -30% [32, 33]. The most common adverse reaction was neutropenia and thrombocytopenia. Lenalidomide (25 mg) in aggressive B-cell lymphoma 1/2 test, 10 days plus sufficient quantities RCHOP-21 program is feasible, will not delay the treatment [34]. The results of in the pomalidomide and actimid-patients with aggressive lymphoma has not been reported.
Proteasome inhibitors interfere with the ubiquitin - proteasome pathway for the degradation of proteins in eukaryotic cells is very important. Many proteins involved in cell cycle regulation of apoptosis and activation of the transcription factor (which is the protease mediates its degradation substrates), making interference ubiquitin - proteasome pathway has become a very attractive strategy for cancer treatment. As the first protease inhibitor, bortezomib main toxicity was thrombocytopenia and peripheral neuropathy. Mantle cell lymphoma is the most sensitive to bortezomib lymphoma. The bortezomib the bortezomib monotherapy DLBCL effect disappointing. However, because the nuclear factor ?B (an inhibitor of nuclear factor - I?B is a substrate of the 26S proteasome, caused by the proteasome inhibitor I?B stability leads to nuclear factor-?B activity weakened kappa B stability of the proteasome inhibitor for treating high expression of the NF?B family target genes tumor a highlight of this tumor include the ABC subtype DLBCL [19] [35] in the study of a small sample of the 27 DLBCL patients, compared with the GBC subtypes, bortezomib combination chemotherapy ABC subtype better efficiency (83% vs 13%; p <0.001) and the median survival time (10.8 months vs 3.4 months; p = 0.003), which showed that bortezomib ABC subtype DLBCL rather than the effect of chemotherapy in GBC subtypes of DLBCL, and provides different treatment for different genetic types of DLBCL patients if this was confirmed, CHOP-like program with Bortezomib United will be the first of two major biological DLBCL The Isoform provided representative of the different regimens. downward NF?B through other strategies still is not feasible, for example, I? kinase and janus signal kinase inhibitors.
Several clinical trials in the treatment of lymphoma proteasome inhibitors include: of MLN9708 (NCT00893464), CEP-18770 (NCT00572637), carfilzomib in PR-047 and NPI-0052. Although these molecules are in vitro proteasome inhibitor, but they are different from the enzyme binding kinetics will lead to differences in the efficacy and safety. Although these drugs with bortezomib bortezomib efficacy can not be compared, but the cell lines in vitro results are still encouraging [36].
mTOR kinase (rapamycin target) in a mammal is a critical growth signals medium, which comes from phosphatidyl alcohol 3 kinase (PI3K). PI3K activation via AKT mTOR expression increases, and its expression can be suppressed by the AMP-activated protein kinase system. downstream target of mTOR, p70 S6 kinase and 4E binding protein is an important regulator of protein synthesis, and is able to control the cell cycle by up-regulating cyclin-D1. Can inhibit mTOR, rapamycin (also known as sirolimus) it first as an immunosuppressant was found, it can hinder the PI3K signaling system oncogenic transformation and tumor progression. The study found that the mTOR activation pathways involved in a variety of tumors, which makes the mTOR inhibitor to enter clinical trials. Temsirolimus and everolimus have been allowed to treat kidney cancer. 20 relapsed or refractory DLBCL patients, the application of everolimus 7 [37]. Relapsed or refractory mantle cell lymphoma patients in a randomized study, the researchers conducted a remedial treatment, results showed the special cancer fitness good effect [38], which makes it was approved in 2010 to treat recurrent mantle cell lymphoid tumor. The most common side effects are thrombocytopenia, anemia and neutropenia. Non-hematologic side effects including hyperglycemia, hyperlipidemia, and fatigue. 10 cases of 22 patients with diffuse large B-cell lymphoma patients temsirolimus effective [39], ridaforolimus treatment of patients with aggressive lymphoma data no report. The compound is the interference of the pilot phase of the mTOR pathway sirolimus (NCT00776373), Pan - PI3K inhibitor GDC-0941 (NCT00876122), PI3K and mTOR kinase inhibitor GDC-0980 (NCT00854126),, Pan - PI3K/mTOR Inhibitor SF1126 double (NCT00907205), XL765 (PI3K Class I isoforms PI3K/TORC1/TORC2 (NCT00485719) and selective dual inhibitor of the mTOR) and CAL-101 (NCT01088048) [40, 41].
Histone deacetylases (HDACs) a can induce the acetyl detachment histone and non-histone proteins (including transcription factors and chaperones) mediation. (HDACs) both regulation of tumor suppressor gene expression, but also the regulation of activity of transcription factors involved in tumor initiation and progression. The histone acetylation exception is due to the increase in HDAC activity and expression, which is often related and pathological gene repressor and neoplastic transformation. Successfully developed the HDAC inhibitors include: the hydroxamate, cyclic peptide, an aliphatic acid, benzene amides. HDAC inhibitors Vorinostat has been approved by the FDA for the treatment of relapsed or refractory cutaneous T-cell lymphoma [42]. Vorinostat and other drugs have a synergistic and cumulative effects, but its efficacy in the treatment of DLBCL and mantle cell lymphoma remains uncertain. Its side effects include diarrhea, nausea, fatigue, hair loss, thrombocytopenia and neutropenia. Belinostat is an HDAC hydroxamate in Phase I trials, it DLBCL patients [43]. Romidepsin (depsipetide) [44] is a Class 1 and Class 2 HDACs selective inhibitor, it can cooperate with belinostat joint bortezomib it has been approved by the FDA for the treatment of recurrent cutaneous T-cell lymphoma, mantle cell lymphoma cell lines anti-tumor effect [45]. Table 4 lists the other HDACs inhibitors in clinical trials.
Endogenous cell death pathway, also called the mitochondrial apoptotic pathway, which is induced by the many signals within the mitochondria. One of the most important regulatory substance belongs to the B-cell lymphoma 2 (Bcl-2) family. The family members of the anti-apoptotic Bcl-2, Bcl-B, Bcl-Xl, A1 and Mcl-1 have the same Bcl-2 homology regions 1-4. Apoptotic effect of multi-domain family members of Bax and Bak and the BH3 protein, Bad, Bik, Bid, Bim, Bmf, HrK, Noxa, and Puma jointly mediated. Once activated, Bax and Bak to induce cytochrome C into the cytoplasm, thereby activating enzyme cascade induce apoptosis. Anti-apoptotic Bcl-2 family members inhibit the release of cytochrome C by preventing the activation of Bax and Bak. Apoptotic BH3 protein binding and release of Bax and Bak in Bax and Bak upstream through the Bcl-2 protein [46]. 40% of DLBCL overexpression of Bcl-2.
The first clinical trial of the Bcl-2 antisense oligonucleotide is oblimersen, two partial remission after the application of the seven patients with DLBCL; However, he seems more effective indolent lymphoma [47]. Small molecule Bcl-2 inhibitor, of Bad-like BH3 and Bcl-2, Bcl-Xl, and expression of Bcl-W binding and release of the Bcl-2 family of pro-apoptotic members induce apoptosis. Experiments underway ABT-263 and ABT-737 in the treatment of lymphoma and small cell lung cancer [48,49]. The main toxicity is dose-dependent acute thrombocytopenia.
The Survivin inhibitor of apoptosis protein a double effect, its function involves blocking apoptosis and regulation of cell mitosis. Survivin is expressed on the majority of human tumors, but not expressed in normal cells. Cancer patients have a spontaneous anti-survivin T-cell response, which makes survival factors to become a very good target for anti-tumor immunotherapy [50] YM155 is a survival inhibitors, it can enhance rituximab anti-tumor of DLBCL role, and 1/2 test, making non-Hodgkin's lymphoma patients in remission for eight months to 48 months [51]. The side effects have elevated serum creatinine stomatitis, fever, nausea, and reversible.
Heat shock proteins are cell growth, differentiation and survival must chaperone. The inhibition of heat shock protein will lead to a so-called client proteins such as: kinase, signal transduction proteins and mutant tumorigenic protein degradation.
Tyrosine kinase inhibitors to block tyrosine kinase involved in the intracellular signal processing. These inhibitors can block one or more signal transduction (multi-tyrosine kinase inhibitor). Protein kinase C ß (PKCß) is a key enzyme, which are many subtypes of lymphoma overexpressed in B cell signaling and survival. Enzastaurin is an oral serine, threonine kinase inhibitor, in vitro by inhibiting PKCß, PI3K and AKT signaling pathway, induction of apoptosis, decreased cell proliferation and inhibits tumor-induced angiogenesis. Moreover, PKCß expression has been reported as a wizard prognosis of DLBCL patients [52]. Enzastaurin mantle cell lymphoma and DLBCL effective [53, 54]. Its side effects were fatigue, edema, headache, movement neuralgia and thrombocytopenia. Currently, a large international trials are evaluating complete remission consolidation therapy in the treatment Enzastaurin as high-risk patients with DLBCL line RCHOP.
Syk is a tyrosine kinase involved in B-cell and T-cell antigen receptor signal transduction. Fostamatinib an oral Syk inhibitor, it is well tolerated in the 23 patients with DLBCL efficient bit of 22% and a complete remission [55]. The Tipifarnib a farnesyl transferase inhibitors the of its mantle cell lymphoma [56].
Aurora kinase family has three members, aurora A, B, C. Aurora A, B intermediary is necessary for cell division, which makes it an ideal therapeutic targets.
Cyclin-dependent protein kinases (CDKs) are often overexpressed in cancer cells. Alvocidib (also known as flavopiridol) is an effect of chronic lymphocytic leukemia pan-CDK inhibitor [57], in a 1/2 clinical trial in 10 relapsed or refractory DLBCL patients, it makes a partial response [58]. The major side effects neutropenia, vomiting and diarrhea
Medchemexpress Can provide the above product,its website:www.medchemexpress.com
Thalidomide and its derivatives represent a class of anti-inflammatory, anti-angiogenic and immunomodulatory properties of anticancer drugs. Targeting tumor cells by direct cytotoxicity and indirect interference tumor microenvironment. The anti-tumor activity of its parent compound thalidomide analogues fairly even stronger, but neurotoxicity smaller. These analogues including multiple myeloma and bone marrow dysplasia syndrome effectively lenalidomide, pomalidomide and actimid. Based on in vitro data, it seems able to see that in addition to inhibition of regulatory T cells, effector T cells Total stimulation and activation of natural killer cells other than the anti-proliferative effects and cell factor (tumor necrosis factor a, interleukin-6, interleukin-8, vascular endothelial growth factor) cut is the most important for the survival and growth of hematological malignancies. Class of immunomodulatory drugs that inhibit angiogenesis and by inhibiting the AKT pathway and enhance the expression of the P21 tumor suppressor genes play a direct anti-tumor proliferation. These in vitro experiments, however, not yet been confirmed by in vivo experiments. Taking into account the complex interactions in vivo immunoregulatory cytokines, and many of the in vitro experiment has not yet been elaborated. In phase II trials, to lenalidomide for relapsed or refractory DLBCL effective rate of 20% -30% [32, 33]. The most common adverse reaction was neutropenia and thrombocytopenia. Lenalidomide (25 mg) in aggressive B-cell lymphoma 1/2 test, 10 days plus sufficient quantities RCHOP-21 program is feasible, will not delay the treatment [34]. The results of in the pomalidomide and actimid-patients with aggressive lymphoma has not been reported.
Proteasome inhibitors interfere with the ubiquitin - proteasome pathway for the degradation of proteins in eukaryotic cells is very important. Many proteins involved in cell cycle regulation of apoptosis and activation of the transcription factor (which is the protease mediates its degradation substrates), making interference ubiquitin - proteasome pathway has become a very attractive strategy for cancer treatment. As the first protease inhibitor, bortezomib main toxicity was thrombocytopenia and peripheral neuropathy. Mantle cell lymphoma is the most sensitive to bortezomib lymphoma. The bortezomib the bortezomib monotherapy DLBCL effect disappointing. However, because the nuclear factor ?B (an inhibitor of nuclear factor - I?B is a substrate of the 26S proteasome, caused by the proteasome inhibitor I?B stability leads to nuclear factor-?B activity weakened kappa B stability of the proteasome inhibitor for treating high expression of the NF?B family target genes tumor a highlight of this tumor include the ABC subtype DLBCL [19] [35] in the study of a small sample of the 27 DLBCL patients, compared with the GBC subtypes, bortezomib combination chemotherapy ABC subtype better efficiency (83% vs 13%; p <0.001) and the median survival time (10.8 months vs 3.4 months; p = 0.003), which showed that bortezomib ABC subtype DLBCL rather than the effect of chemotherapy in GBC subtypes of DLBCL, and provides different treatment for different genetic types of DLBCL patients if this was confirmed, CHOP-like program with Bortezomib United will be the first of two major biological DLBCL The Isoform provided representative of the different regimens. downward NF?B through other strategies still is not feasible, for example, I? kinase and janus signal kinase inhibitors.
Several clinical trials in the treatment of lymphoma proteasome inhibitors include: of MLN9708 (NCT00893464), CEP-18770 (NCT00572637), carfilzomib in PR-047 and NPI-0052. Although these molecules are in vitro proteasome inhibitor, but they are different from the enzyme binding kinetics will lead to differences in the efficacy and safety. Although these drugs with bortezomib bortezomib efficacy can not be compared, but the cell lines in vitro results are still encouraging [36].
mTOR kinase (rapamycin target) in a mammal is a critical growth signals medium, which comes from phosphatidyl alcohol 3 kinase (PI3K). PI3K activation via AKT mTOR expression increases, and its expression can be suppressed by the AMP-activated protein kinase system. downstream target of mTOR, p70 S6 kinase and 4E binding protein is an important regulator of protein synthesis, and is able to control the cell cycle by up-regulating cyclin-D1. Can inhibit mTOR, rapamycin (also known as sirolimus) it first as an immunosuppressant was found, it can hinder the PI3K signaling system oncogenic transformation and tumor progression. The study found that the mTOR activation pathways involved in a variety of tumors, which makes the mTOR inhibitor to enter clinical trials. Temsirolimus and everolimus have been allowed to treat kidney cancer. 20 relapsed or refractory DLBCL patients, the application of everolimus 7 [37]. Relapsed or refractory mantle cell lymphoma patients in a randomized study, the researchers conducted a remedial treatment, results showed the special cancer fitness good effect [38], which makes it was approved in 2010 to treat recurrent mantle cell lymphoid tumor. The most common side effects are thrombocytopenia, anemia and neutropenia. Non-hematologic side effects including hyperglycemia, hyperlipidemia, and fatigue. 10 cases of 22 patients with diffuse large B-cell lymphoma patients temsirolimus effective [39], ridaforolimus treatment of patients with aggressive lymphoma data no report. The compound is the interference of the pilot phase of the mTOR pathway sirolimus (NCT00776373), Pan - PI3K inhibitor GDC-0941 (NCT00876122), PI3K and mTOR kinase inhibitor GDC-0980 (NCT00854126),, Pan - PI3K/mTOR Inhibitor SF1126 double (NCT00907205), XL765 (PI3K Class I isoforms PI3K/TORC1/TORC2 (NCT00485719) and selective dual inhibitor of the mTOR) and CAL-101 (NCT01088048) [40, 41].
Histone deacetylases (HDACs) a can induce the acetyl detachment histone and non-histone proteins (including transcription factors and chaperones) mediation. (HDACs) both regulation of tumor suppressor gene expression, but also the regulation of activity of transcription factors involved in tumor initiation and progression. The histone acetylation exception is due to the increase in HDAC activity and expression, which is often related and pathological gene repressor and neoplastic transformation. Successfully developed the HDAC inhibitors include: the hydroxamate, cyclic peptide, an aliphatic acid, benzene amides. HDAC inhibitors Vorinostat has been approved by the FDA for the treatment of relapsed or refractory cutaneous T-cell lymphoma [42]. Vorinostat and other drugs have a synergistic and cumulative effects, but its efficacy in the treatment of DLBCL and mantle cell lymphoma remains uncertain. Its side effects include diarrhea, nausea, fatigue, hair loss, thrombocytopenia and neutropenia. Belinostat is an HDAC hydroxamate in Phase I trials, it DLBCL patients [43]. Romidepsin (depsipetide) [44] is a Class 1 and Class 2 HDACs selective inhibitor, it can cooperate with belinostat joint bortezomib it has been approved by the FDA for the treatment of recurrent cutaneous T-cell lymphoma, mantle cell lymphoma cell lines anti-tumor effect [45]. Table 4 lists the other HDACs inhibitors in clinical trials.
Endogenous cell death pathway, also called the mitochondrial apoptotic pathway, which is induced by the many signals within the mitochondria. One of the most important regulatory substance belongs to the B-cell lymphoma 2 (Bcl-2) family. The family members of the anti-apoptotic Bcl-2, Bcl-B, Bcl-Xl, A1 and Mcl-1 have the same Bcl-2 homology regions 1-4. Apoptotic effect of multi-domain family members of Bax and Bak and the BH3 protein, Bad, Bik, Bid, Bim, Bmf, HrK, Noxa, and Puma jointly mediated. Once activated, Bax and Bak to induce cytochrome C into the cytoplasm, thereby activating enzyme cascade induce apoptosis. Anti-apoptotic Bcl-2 family members inhibit the release of cytochrome C by preventing the activation of Bax and Bak. Apoptotic BH3 protein binding and release of Bax and Bak in Bax and Bak upstream through the Bcl-2 protein [46]. 40% of DLBCL overexpression of Bcl-2.
The first clinical trial of the Bcl-2 antisense oligonucleotide is oblimersen, two partial remission after the application of the seven patients with DLBCL; However, he seems more effective indolent lymphoma [47]. Small molecule Bcl-2 inhibitor, of Bad-like BH3 and Bcl-2, Bcl-Xl, and expression of Bcl-W binding and release of the Bcl-2 family of pro-apoptotic members induce apoptosis. Experiments underway ABT-263 and ABT-737 in the treatment of lymphoma and small cell lung cancer [48,49]. The main toxicity is dose-dependent acute thrombocytopenia.
The Survivin inhibitor of apoptosis protein a double effect, its function involves blocking apoptosis and regulation of cell mitosis. Survivin is expressed on the majority of human tumors, but not expressed in normal cells. Cancer patients have a spontaneous anti-survivin T-cell response, which makes survival factors to become a very good target for anti-tumor immunotherapy [50] YM155 is a survival inhibitors, it can enhance rituximab anti-tumor of DLBCL role, and 1/2 test, making non-Hodgkin's lymphoma patients in remission for eight months to 48 months [51]. The side effects have elevated serum creatinine stomatitis, fever, nausea, and reversible.
Heat shock proteins are cell growth, differentiation and survival must chaperone. The inhibition of heat shock protein will lead to a so-called client proteins such as: kinase, signal transduction proteins and mutant tumorigenic protein degradation.
Tyrosine kinase inhibitors to block tyrosine kinase involved in the intracellular signal processing. These inhibitors can block one or more signal transduction (multi-tyrosine kinase inhibitor). Protein kinase C ß (PKCß) is a key enzyme, which are many subtypes of lymphoma overexpressed in B cell signaling and survival. Enzastaurin is an oral serine, threonine kinase inhibitor, in vitro by inhibiting PKCß, PI3K and AKT signaling pathway, induction of apoptosis, decreased cell proliferation and inhibits tumor-induced angiogenesis. Moreover, PKCß expression has been reported as a wizard prognosis of DLBCL patients [52]. Enzastaurin mantle cell lymphoma and DLBCL effective [53, 54]. Its side effects were fatigue, edema, headache, movement neuralgia and thrombocytopenia. Currently, a large international trials are evaluating complete remission consolidation therapy in the treatment Enzastaurin as high-risk patients with DLBCL line RCHOP.
Syk is a tyrosine kinase involved in B-cell and T-cell antigen receptor signal transduction. Fostamatinib an oral Syk inhibitor, it is well tolerated in the 23 patients with DLBCL efficient bit of 22% and a complete remission [55]. The Tipifarnib a farnesyl transferase inhibitors the of its mantle cell lymphoma [56].
Aurora kinase family has three members, aurora A, B, C. Aurora A, B intermediary is necessary for cell division, which makes it an ideal therapeutic targets.
Cyclin-dependent protein kinases (CDKs) are often overexpressed in cancer cells. Alvocidib (also known as flavopiridol) is an effect of chronic lymphocytic leukemia pan-CDK inhibitor [57], in a 1/2 clinical trial in 10 relapsed or refractory DLBCL patients, it makes a partial response [58]. The major side effects neutropenia, vomiting and diarrhea
Medchemexpress Can provide the above product,its website:www.medchemexpress.com