Research progress of new molecular targeted anti-cancer drugs
Research progress of new molecular targeted anti-cancer drugs
With the aging of the population trends and the aggravation of environmental pollution, cancer is increasingly becoming the enemy threat to human health. Since the beginning of the new century, the treatment of cancer there is a new "weapon" - molecular targeted anti-cancer drugs. Unlike traditional cytotoxic drugs, these drugs against normal cells do not express or rarely expressed in tumor cell growth and proliferation in the presence of certain specific molecule or structure of loci (i.e., the target), it can be the specificity of act on the tumor cells. Molecular targeted therapy represents the latest development direction of Cancer, This article describes a few hot areas of new research progress.
Cell signal transduction pathway as a target for anticancer drugs
The intracellular signal transduction pathways are woven into a complex and very orderly network system, to disrupt tumor cells in the system in an orderly due to the interference of the external environment, and gene mutation factors. Certain molecules of cellular signal transduction pathway as a target, selectively block tumor cell autocrine or paracrine signaling pathway is an important direction of the anti-cancer drug development.
Protein tyrosine kinase as a tumor therapeutic targets
Protein tyrosine kinase (PTK) is a group of proteins involved in normal cell growth and tumor cell malignant transformation, recent studies have found increased its activity is one of the hallmarks of the malignant cells, many tests proved PTK involved in the abnormal signal transduction the occurrence and development of a variety of tumor directly associated PTK inhibitors are useful in the treatment of Clinical Oncology. Epidermal growth factor receptor (EGFR) is an important one in the PTK superfamily, including erbB1, erbB2, erbB3 and erbB4 four-membrane glycoprotein (often referred to as the Her1, Her2, Her3 and HER4), the inhibitor of EGFR receptor tyrosine kinase inhibitors is mainly divided into two categories: monoclonal antibodies and small molecules, monoclonal antibodies and competitive ligand binding EGFR, PTK inhibition of ligand-activated EGFR and promote EGFR endocytosis, thereby generating the anti-tumor effect; small molecule compounds combined with the EGFR intracellular the 4TP binding sites, inhibiting the PTK phosphorylation, blocking waterfall signal transmission. Both see clinical efficacy have been reported.
Monoclonal antibody against B-cell CD20 antigen / mouse chimeric monoclonal antibody, rituximab, infliximab (rituximab) and CD52 antigen (alemtuzumab), alemtuzumab, antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cell cytotoxicity (CDC) efficient killing tumor cells has been approved by the FDA listed, respectively, for recurrence, chemotherapy tolerance of non-Hodgkin's lymphoma and fludarabine-resistant chronic lymphocytic the treatment of leukemia (CLL). In addition to the blood system tumors, a lot of monoclonal antibody drugs currently under development for solid tumors, the most representative is developed by Genentech, Inc., USA trastuzumab (trastuzumab), for Her2/neu proto-oncogene product specific role in HER2 receptor overexpression in breast cancer cells, clinical studies have shown that treatment of metastatic day erg overexpressing breast cancer, trastuzumab with chemotherapy efficiency of 57% to 64%. Cetuximab (cetuximab), panitumumab, have developed matuzumab the monoclonal antibody for advanced colorectal cancer, and squamous cell carcinoma of the head and neck and non-small cell lung cancer (NSCLC), which panitumumab and matLzumab, fully humanized monoclonal antibodies. In September 2006, the panitumumab been FDA approved for the treatment of metastatic colorectal cancer. Treatment of breast cancer drug pertuzumab combined with HER2 receptor extracellular region ? inhibit dimer formation, inhibition of receptor-mediated signal transduction pathway A ray of hope for patients with Herg low expression, is currently in Phase II clinical trials.
In addition to these non-conjugated monoclonal antibody, anti-tumor monoclonal antibody drugs include a combination of drugs known as immune conjugate, connected by a "bullet" substances (radionuclides, drugs and toxins) and monoclonal antibody, respectively constitute radioimmunoassay conjugates, chemical immunoconjugates and immunotoxins. Jim monoclonal antibody (gemtnzumab,) by the humanized CD33 antibody coupled with the antitumor antibiotic calicheamicin (calicheamicin) from the first monoclonal antibody approved for listing conjugate, mainly for acute myelogenous leukemia treatment. Radioimmunoassay conjugates alternate Tiuxetan (ibritumomab), and tositumomab (tositumomab) targeting CD20, respectively binding the isotope 90Y and 131 ? these immunoconjugates into tumor cells, lethality, broad application prospects.
Small molecule inhibitors, the first success of the Bcr-Abl protein tyrosine kinase inhibitor imatinib imatinib (imatinib, Gleevec) oral formulations. Clinical studies have shown, for chronic myeloid leukemia (CIVIL) treatment, almost 100% availability of efficacy, and imatinib treatment of gastrointestinal stromal tumor (GIST) has also made a breakthrough, but long-term use there is a resistance issues. Therefore, to overcome the resistance, to find a more effective preparation is essential; new generation of nilotinib by imatinib transformation of Nigeria by the molecular structure, and its intensity increased by 30 times, imatinib-resistant Bcr-Abl mutations caused by imatinib tumor drug. Dasatinib and nilotinib are still in Phase II clinical study of the same type drugs,.
Gefitinib the Nigerian (gefitinib, Iressa) and elotinib (Tarceva) is two targeted oral small molecule EGFR tyrosine kinase inhibitors, mainly for NSCLC, second-and third-line treatment, due to a more in-depth research, clinical applications are more mature, so their reports are very detailed. Randomized, double-blind, Phase II IDEAL1 and old the EAL2 studies have shown that gefitinib as second and third line monotherapy in NSCLC effective rate was 18.4%, 40% to 50% of cancer patients progression, more than 40% improved symptoms, This is the traditional cytotoxic drugs can not be compared. Gefitinib in combination with chemotherapy has served as the ideal model to improve the efficacy, but INTACT-1 and INTACT-2 two Phase III clinical but proved gefitinib erlotinib and gemcitabine gemcitabine + cisplatin or paclitaxel + carboplatin combination, and simple chemotherapy compared the efficacy and survival rate of the patients with NSCLC and has not been improved. Affect the response rate and prognostic factors, the importance of gender, pathological type and smoking history has been affirmed, female, adenocarcinoma, and no history of smoking Asian patients with good prognosis.
Tumor signal transduction is a complex, multifactorial network systems, inhibition of a single signal often not enough to curb the development of tumors, clinical studies have shown that multi-target joint block better than a single target for suppression. Novel multi-targeted anticancer drugs sorafenib (sorafenib), with double anti-tumor effect, on the one hand inhibit Raf / MEK / ERK pathway, direct inhibition of tumor growth by inhibiting VEGF and PDGF receptor; On the other hand, blocking tumor angiogenesis, indirectly inhibit tumor growth, an advanced kidney cancer the Sichuan clinical studies have shown that sorafenib significantly slow disease progression can significantly prolong survival, is the first approved by the FDA in the last 20 years the treatment of advanced renal cell carcinoma drugs. Lapatinib (lapatinib) at the same time acting on the HER1 and HERG gene, blocking downstream signal transduction through their homo-or heterodimers, the second after trastuzumab breast cancer molecular targeted drugs, the latest clinical trials become a hot topic of the 2006 ASCO meeting. Other multi-target inhibition the drugs vadetanib, sunitinib, canertinib and.
Ras proteins as targets of anti-tumor effect
Ras-Raf-MEK-ERK pathway, the Ras protein is to the important transduction proteins that regulate cell growth, the Ras mutation rate, human tumors in approximately 30% exists, common in pancreatic cancer, colon cancer, lung cancer, etc.. Ras protein precursor synthesized in the cytoplasm To locate the cell membrane biological effect modifications need to be translated, the key step is farnesylation, farnesyl transferase catalyzed farnesyl pyrophosphate Transfer a ester (FPP) Fanijiji group to Ras protein C terminal cysteine ??residue, farnesyl transferase inhibitors (FTI) for the activation of Ras mutant cells may be inhibited. Thereby synthesizing a series of FTI, tipifarnib (Zarnestra), lonafarnib (Sarasar) and BMS-214662. While these drugs show a good anti-tumor activity both in vitro and in mouse xenograft test, but the results of clinical studies are not satisfactory, the pre-obtained for the strong inhibition of tumor cells has not been validated, with the traditional chemotherapy drug compared to its no significant effect. For some of its downstream transduction molecule targeted drugs may have value for development, such as inhibitors of Raf and MEK inhibitor.
Anti-angiogenesis in cancer therapy
Folkman first proposed in 1971 after the infiltration of tumor growth depends on angiogenesis, with the gradual deepening of the research in this field, an endless stream of treatment strategies for tumor angiogenesis, there are more than 30 kinds of anti-angiogenesis drug undergoing clinical study .
Inhibition of vascular endothelial growth factor activation
At the core of vascular endothelial growth factor (VEGF) in tumor angiogenesis can be secreted by many tumor cells, is a major inducer of angiogenesis. Vascular endothelial cells of the VEGF-mediated signal transduction is achieved through the high affinity receptor tyrosine kinases, and blocking the sites which can effectively inhibit tumor angiogenesis.
Humanized VEGF monoclonal antibody bevacizumab (bevacizu-mab), and a variety of VEGF isoforms with high affinity and can be combined with the secretion of VEGF and its receptor, blocking signal transduction, anti-tumor effect. Bevacizumab with IFL program (irinotecan Kang + fluorouracil + formic acid tetrahydro leucovorin) for advanced colorectal cancer study shows that the combined treatment group and the chemotherapy group response rates were 45% and 35%, the median survival period were 20.3 and 15.6 months. Bevacizumab by FDA in 2004 for the first-line treatment of metastatic colorectal cancer, the FDA approved the first drug inhibition of angiogenesis. After ECOG3200 research, the FOLFOX4 program bevacizumab can improve the efficiency of the treatment of advanced colorectal cancer, the median survival rate and disease progression-free survival.
Development of small molecule inhibitors, in addition to selectivity for VEGFR tyrosine kinase, multi-target drugs such as vadetanib, sorafenib is the focus of current research.
Inhibit the degradation of the basement membrane
The extracellular protease plays an important role in the regulation of angiogenesis and tumor invasion and metastasis. Matrix-degrading enzyme release after the destruction of the basement membrane, endothelial cell migration and invasion of extracellular matrix (ECM), the formation of capillary-like structures. Matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) ECM synthesis and degradation metabolic balance two important factors, both adjust the imbalance to promote tumor angiogenesis and metastasis. Early development value several MMP inhibitors, such as marimastat, prinomastat, batimastat, BIAS-275291, BAY12-9956, neovastat and metastat Phase III clinical studies have shown that it can not improve the survival rate of patients now have stopped further development. TIMP synthetic research began in the 1980s, TIMP clinical effect of the poor, little is known about the exact mechanism of MMP in angiogenesis and tumorigenesis may MMP family is too large, MM corpse inhibitors only by targeting the part of MMPs; angiogenesis and metastasis in advanced cancer has already been completed, MMP role is limited, the other MM dead inhibitors can cause severe toxicity, which affected its clinical application.
Direct inhibition of endothelial cells
Angiogenesis inhibitors directly target tumor vascular endothelial cells, and its obvious advantages. First, the vascular endothelial cell is directly exposed to the blood circulation, the drug without entering inside the tumor tissue, can play a role in target cells, and endothelial cells is relatively stable genetic diploid cells, repeated administration is not easy to produce drug resistance , in addition to destroying a capillary perfusion area can make it all the tumor cells with acute ischemic necrosis, to suppress high efficiency.
Endostatin (endostatin) endostatin, an endogenous angiogenesis inhibitors, and can specifically inhibit the proliferation of endothelial cells, the decrease in tumor angiogenesis and inhibition of tumor metastasis, non-toxic to normal cells and generally does not resistance. China since 1998 for the development of anti-endostatin (ex degrees, YH-16) in the recombinant human vascular Phase II clinical observation YH-16 plus vinorelbine and cisplatin (NP regimen) in the treatment of advanced NSCLC efficacy. YH-16 Joint NP regimen than the single NP program, to increase the efficacy and side effects. Recent Phase III prospective, double-blind, controlled clinical study further confirmed its clinical efficacy, the State Food and Drug Administration (SFDA) YH-16 was approved in September 2005 for the treatment of NSCLC. Folkman, endostatin spectrum anti-tumor targets of a variety of vascular generated regulatory genes (over 12%) of the genome of human vascular endothelial cells have a role, and the mice trials have shown, the side effects of the current the smallest in the anticancer drugs, combination therapy with other therapies.
Endothelial cells angiogenesis inhibitor TNP-470 (fumagillin derivatives), thalidomide (thalidomide), cyclooxygenase -2 (COX-2) inhibitors plug to celecoxib (Celebrex ) and so on.
The anti-angiogenic therapy topics at the forefront of the field of medical oncology, its inevitable there will be academic dispute. Some scholars have questioned whether it will damage the normal angiogenesis, such as reparative angiogenesis, vascular inhibit the formation of the hypoxic microenvironment will filter out the higher malignant tumor cells. The Jain and Kerbel study, an appropriate amount of angiogenesis inhibitors can make the blood vessels of the tumor cells tends to be "normalized" to improve the blood supply and oxygen, which will also help full access to chemotherapy drugs and tumor cells, to achieve a better therapeutic effect. Conventional radiotherapy, chemotherapy application, as an integral part of the comprehensive treatment of the tumor, will be the direction of the development of angiogenesis inhibitors. The one hand, angiogenesis inhibitors have the potential to improve the efficacy of radiotherapy, on the other hand received traditional treatment in patients with tumor regression period, the application of angiogenesis inhibitors may micrometastases in a resting state, thereby inhibiting tumor metastasis and recurrence.
Cell cycle control agent
The cell cycle is the basic process of cellular activities, the evolutionary process of cell development and the establishment of a more complex and sophisticated control mechanisms to ensure strict and orderly cell cycle alternately and each phase is sequentially changed. Cyclin-dependent kinase (CDK) is the core of the regulatory network of leading cycle start, and results. Cell cycle regulatory proteins (cyclin) positively regulates CDK, cyclin-dependent kinase inhibitor (CKI) from the negative regulatory role. Studies have shown that in a variety of tumor occurrence and development of CDK / cyclin overexpression or endogenous inhibitors, such as the decline in p16 expression or the pRb gene mutations, CDK activity can lead to loss of control, uncontrolled growth . CDK key role in the cell cycle caused by the development block cell cycle progression and induction of growth arrest-specific kinase inhibitor CDK inhibitors have a strong interest.
CDK regulation of key DNA integrity control monitoring points (CHK). When DNA damage, cell arrest in the G1 phase, S or G2 phase, to provide sufficient time to repair DNA. Anticancer drugs by breaking DNA, destruction of tumor cells while also activates chk, there is a small part of the tumor cells in drug-induced cycle arrest after repair system is able to activate and continue to survive, thereby reducing the efficacy of the drug. People trying to weaken tumor cells chk enhance normal cell chk role to improve the effect of chemotherapy. Such as more than 50% of tumor cells in the presence of a p53 mutation or deletion, lack G1 phase CHK advantage of this feature, the cell cycle can be modified, the specific design of the treatment, so that normal cells blocked in G1 phase, in order to improve the S phase-specific selective killing effect of the drug on tumor cells.
The present study is more cell cycle control agent flavopiridol and UCN-01. The U.S. National Cancer Institute (NCI) screened flavopiridolf261 is derived from a plant flavonoids, can compete with ATP binding sites, broad-spectrum inhibition of CDK role, including CDK1, 2, 4, 6, 7, also blocking the cell cycle in G1 and G2 phase, inhibit the activity of a variety of solid tumor cell proliferation. Flavopiridol with paclitaxel, gemcitabine, cisplatin in combination synergies, these chemotherapy drugs can inhibit the synthesis of DNA, the cells effectively concentrated in the S phase, can be the Flavopiridol mediated CDK inhibition improve their cells. cytotoxicity.
Epilogue
Very hot topic in the past two years, medical oncology community is the problem of multi-target drugs and combination therapy. The complex mechanism of the formation of solid tumors, the tumor tissue may be derived from a single gene mutation, but its growth potential new mutations, the course of treatment will produce drug resistance and effective method is the same time more than one key exception the joint intervention of the gene, so that not only can improve the therapeutic effect and to reduce the molecular resist the formation of dangerous clinical efficacy of sunitinib, sorafenib, is proof of this theory; another effective strategy is combination therapy, including targeted drug in combination with chemotherapy drugs, targeted drugs have a synergistic effect. The van Cruijsen pointed out that the inhibition of VEGF (R) and EGF (R) pathway, to avoid the potential for enhanced resistance to EGFR inhibitors of angiogenesis, can also make the anti-angiogenic effect is more significant. The superiority of the cell cycle inhibitor drugs in combination with cytotoxic drugs have been explained in the text. Of course, these theories are only a preliminary study the clinical needs deeper study and long-term observation, such as regimen is sequential administration or administration at the same time better, the order of administration, optimal dose and side effects comprehensive research, will have a convincing judgment.
With the aging of the population trends and the aggravation of environmental pollution, cancer is increasingly becoming the enemy threat to human health. Since the beginning of the new century, the treatment of cancer there is a new "weapon" - molecular targeted anti-cancer drugs. Unlike traditional cytotoxic drugs, these drugs against normal cells do not express or rarely expressed in tumor cell growth and proliferation in the presence of certain specific molecule or structure of loci (i.e., the target), it can be the specificity of act on the tumor cells. Molecular targeted therapy represents the latest development direction of Cancer, This article describes a few hot areas of new research progress.
Cell signal transduction pathway as a target for anticancer drugs
The intracellular signal transduction pathways are woven into a complex and very orderly network system, to disrupt tumor cells in the system in an orderly due to the interference of the external environment, and gene mutation factors. Certain molecules of cellular signal transduction pathway as a target, selectively block tumor cell autocrine or paracrine signaling pathway is an important direction of the anti-cancer drug development.
Protein tyrosine kinase as a tumor therapeutic targets
Protein tyrosine kinase (PTK) is a group of proteins involved in normal cell growth and tumor cell malignant transformation, recent studies have found increased its activity is one of the hallmarks of the malignant cells, many tests proved PTK involved in the abnormal signal transduction the occurrence and development of a variety of tumor directly associated PTK inhibitors are useful in the treatment of Clinical Oncology. Epidermal growth factor receptor (EGFR) is an important one in the PTK superfamily, including erbB1, erbB2, erbB3 and erbB4 four-membrane glycoprotein (often referred to as the Her1, Her2, Her3 and HER4), the inhibitor of EGFR receptor tyrosine kinase inhibitors is mainly divided into two categories: monoclonal antibodies and small molecules, monoclonal antibodies and competitive ligand binding EGFR, PTK inhibition of ligand-activated EGFR and promote EGFR endocytosis, thereby generating the anti-tumor effect; small molecule compounds combined with the EGFR intracellular the 4TP binding sites, inhibiting the PTK phosphorylation, blocking waterfall signal transmission. Both see clinical efficacy have been reported.
Monoclonal antibody against B-cell CD20 antigen / mouse chimeric monoclonal antibody, rituximab, infliximab (rituximab) and CD52 antigen (alemtuzumab), alemtuzumab, antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cell cytotoxicity (CDC) efficient killing tumor cells has been approved by the FDA listed, respectively, for recurrence, chemotherapy tolerance of non-Hodgkin's lymphoma and fludarabine-resistant chronic lymphocytic the treatment of leukemia (CLL). In addition to the blood system tumors, a lot of monoclonal antibody drugs currently under development for solid tumors, the most representative is developed by Genentech, Inc., USA trastuzumab (trastuzumab), for Her2/neu proto-oncogene product specific role in HER2 receptor overexpression in breast cancer cells, clinical studies have shown that treatment of metastatic day erg overexpressing breast cancer, trastuzumab with chemotherapy efficiency of 57% to 64%. Cetuximab (cetuximab), panitumumab, have developed matuzumab the monoclonal antibody for advanced colorectal cancer, and squamous cell carcinoma of the head and neck and non-small cell lung cancer (NSCLC), which panitumumab and matLzumab, fully humanized monoclonal antibodies. In September 2006, the panitumumab been FDA approved for the treatment of metastatic colorectal cancer. Treatment of breast cancer drug pertuzumab combined with HER2 receptor extracellular region ? inhibit dimer formation, inhibition of receptor-mediated signal transduction pathway A ray of hope for patients with Herg low expression, is currently in Phase II clinical trials.
In addition to these non-conjugated monoclonal antibody, anti-tumor monoclonal antibody drugs include a combination of drugs known as immune conjugate, connected by a "bullet" substances (radionuclides, drugs and toxins) and monoclonal antibody, respectively constitute radioimmunoassay conjugates, chemical immunoconjugates and immunotoxins. Jim monoclonal antibody (gemtnzumab,) by the humanized CD33 antibody coupled with the antitumor antibiotic calicheamicin (calicheamicin) from the first monoclonal antibody approved for listing conjugate, mainly for acute myelogenous leukemia treatment. Radioimmunoassay conjugates alternate Tiuxetan (ibritumomab), and tositumomab (tositumomab) targeting CD20, respectively binding the isotope 90Y and 131 ? these immunoconjugates into tumor cells, lethality, broad application prospects.
Small molecule inhibitors, the first success of the Bcr-Abl protein tyrosine kinase inhibitor imatinib imatinib (imatinib, Gleevec) oral formulations. Clinical studies have shown, for chronic myeloid leukemia (CIVIL) treatment, almost 100% availability of efficacy, and imatinib treatment of gastrointestinal stromal tumor (GIST) has also made a breakthrough, but long-term use there is a resistance issues. Therefore, to overcome the resistance, to find a more effective preparation is essential; new generation of nilotinib by imatinib transformation of Nigeria by the molecular structure, and its intensity increased by 30 times, imatinib-resistant Bcr-Abl mutations caused by imatinib tumor drug. Dasatinib and nilotinib are still in Phase II clinical study of the same type drugs,.
Gefitinib the Nigerian (gefitinib, Iressa) and elotinib (Tarceva) is two targeted oral small molecule EGFR tyrosine kinase inhibitors, mainly for NSCLC, second-and third-line treatment, due to a more in-depth research, clinical applications are more mature, so their reports are very detailed. Randomized, double-blind, Phase II IDEAL1 and old the EAL2 studies have shown that gefitinib as second and third line monotherapy in NSCLC effective rate was 18.4%, 40% to 50% of cancer patients progression, more than 40% improved symptoms, This is the traditional cytotoxic drugs can not be compared. Gefitinib in combination with chemotherapy has served as the ideal model to improve the efficacy, but INTACT-1 and INTACT-2 two Phase III clinical but proved gefitinib erlotinib and gemcitabine gemcitabine + cisplatin or paclitaxel + carboplatin combination, and simple chemotherapy compared the efficacy and survival rate of the patients with NSCLC and has not been improved. Affect the response rate and prognostic factors, the importance of gender, pathological type and smoking history has been affirmed, female, adenocarcinoma, and no history of smoking Asian patients with good prognosis.
Tumor signal transduction is a complex, multifactorial network systems, inhibition of a single signal often not enough to curb the development of tumors, clinical studies have shown that multi-target joint block better than a single target for suppression. Novel multi-targeted anticancer drugs sorafenib (sorafenib), with double anti-tumor effect, on the one hand inhibit Raf / MEK / ERK pathway, direct inhibition of tumor growth by inhibiting VEGF and PDGF receptor; On the other hand, blocking tumor angiogenesis, indirectly inhibit tumor growth, an advanced kidney cancer the Sichuan clinical studies have shown that sorafenib significantly slow disease progression can significantly prolong survival, is the first approved by the FDA in the last 20 years the treatment of advanced renal cell carcinoma drugs. Lapatinib (lapatinib) at the same time acting on the HER1 and HERG gene, blocking downstream signal transduction through their homo-or heterodimers, the second after trastuzumab breast cancer molecular targeted drugs, the latest clinical trials become a hot topic of the 2006 ASCO meeting. Other multi-target inhibition the drugs vadetanib, sunitinib, canertinib and.
Ras proteins as targets of anti-tumor effect
Ras-Raf-MEK-ERK pathway, the Ras protein is to the important transduction proteins that regulate cell growth, the Ras mutation rate, human tumors in approximately 30% exists, common in pancreatic cancer, colon cancer, lung cancer, etc.. Ras protein precursor synthesized in the cytoplasm To locate the cell membrane biological effect modifications need to be translated, the key step is farnesylation, farnesyl transferase catalyzed farnesyl pyrophosphate Transfer a ester (FPP) Fanijiji group to Ras protein C terminal cysteine ??residue, farnesyl transferase inhibitors (FTI) for the activation of Ras mutant cells may be inhibited. Thereby synthesizing a series of FTI, tipifarnib (Zarnestra), lonafarnib (Sarasar) and BMS-214662. While these drugs show a good anti-tumor activity both in vitro and in mouse xenograft test, but the results of clinical studies are not satisfactory, the pre-obtained for the strong inhibition of tumor cells has not been validated, with the traditional chemotherapy drug compared to its no significant effect. For some of its downstream transduction molecule targeted drugs may have value for development, such as inhibitors of Raf and MEK inhibitor.
Anti-angiogenesis in cancer therapy
Folkman first proposed in 1971 after the infiltration of tumor growth depends on angiogenesis, with the gradual deepening of the research in this field, an endless stream of treatment strategies for tumor angiogenesis, there are more than 30 kinds of anti-angiogenesis drug undergoing clinical study .
Inhibition of vascular endothelial growth factor activation
At the core of vascular endothelial growth factor (VEGF) in tumor angiogenesis can be secreted by many tumor cells, is a major inducer of angiogenesis. Vascular endothelial cells of the VEGF-mediated signal transduction is achieved through the high affinity receptor tyrosine kinases, and blocking the sites which can effectively inhibit tumor angiogenesis.
Humanized VEGF monoclonal antibody bevacizumab (bevacizu-mab), and a variety of VEGF isoforms with high affinity and can be combined with the secretion of VEGF and its receptor, blocking signal transduction, anti-tumor effect. Bevacizumab with IFL program (irinotecan Kang + fluorouracil + formic acid tetrahydro leucovorin) for advanced colorectal cancer study shows that the combined treatment group and the chemotherapy group response rates were 45% and 35%, the median survival period were 20.3 and 15.6 months. Bevacizumab by FDA in 2004 for the first-line treatment of metastatic colorectal cancer, the FDA approved the first drug inhibition of angiogenesis. After ECOG3200 research, the FOLFOX4 program bevacizumab can improve the efficiency of the treatment of advanced colorectal cancer, the median survival rate and disease progression-free survival.
Development of small molecule inhibitors, in addition to selectivity for VEGFR tyrosine kinase, multi-target drugs such as vadetanib, sorafenib is the focus of current research.
Inhibit the degradation of the basement membrane
The extracellular protease plays an important role in the regulation of angiogenesis and tumor invasion and metastasis. Matrix-degrading enzyme release after the destruction of the basement membrane, endothelial cell migration and invasion of extracellular matrix (ECM), the formation of capillary-like structures. Matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) ECM synthesis and degradation metabolic balance two important factors, both adjust the imbalance to promote tumor angiogenesis and metastasis. Early development value several MMP inhibitors, such as marimastat, prinomastat, batimastat, BIAS-275291, BAY12-9956, neovastat and metastat Phase III clinical studies have shown that it can not improve the survival rate of patients now have stopped further development. TIMP synthetic research began in the 1980s, TIMP clinical effect of the poor, little is known about the exact mechanism of MMP in angiogenesis and tumorigenesis may MMP family is too large, MM corpse inhibitors only by targeting the part of MMPs; angiogenesis and metastasis in advanced cancer has already been completed, MMP role is limited, the other MM dead inhibitors can cause severe toxicity, which affected its clinical application.
Direct inhibition of endothelial cells
Angiogenesis inhibitors directly target tumor vascular endothelial cells, and its obvious advantages. First, the vascular endothelial cell is directly exposed to the blood circulation, the drug without entering inside the tumor tissue, can play a role in target cells, and endothelial cells is relatively stable genetic diploid cells, repeated administration is not easy to produce drug resistance , in addition to destroying a capillary perfusion area can make it all the tumor cells with acute ischemic necrosis, to suppress high efficiency.
Endostatin (endostatin) endostatin, an endogenous angiogenesis inhibitors, and can specifically inhibit the proliferation of endothelial cells, the decrease in tumor angiogenesis and inhibition of tumor metastasis, non-toxic to normal cells and generally does not resistance. China since 1998 for the development of anti-endostatin (ex degrees, YH-16) in the recombinant human vascular Phase II clinical observation YH-16 plus vinorelbine and cisplatin (NP regimen) in the treatment of advanced NSCLC efficacy. YH-16 Joint NP regimen than the single NP program, to increase the efficacy and side effects. Recent Phase III prospective, double-blind, controlled clinical study further confirmed its clinical efficacy, the State Food and Drug Administration (SFDA) YH-16 was approved in September 2005 for the treatment of NSCLC. Folkman, endostatin spectrum anti-tumor targets of a variety of vascular generated regulatory genes (over 12%) of the genome of human vascular endothelial cells have a role, and the mice trials have shown, the side effects of the current the smallest in the anticancer drugs, combination therapy with other therapies.
Endothelial cells angiogenesis inhibitor TNP-470 (fumagillin derivatives), thalidomide (thalidomide), cyclooxygenase -2 (COX-2) inhibitors plug to celecoxib (Celebrex ) and so on.
The anti-angiogenic therapy topics at the forefront of the field of medical oncology, its inevitable there will be academic dispute. Some scholars have questioned whether it will damage the normal angiogenesis, such as reparative angiogenesis, vascular inhibit the formation of the hypoxic microenvironment will filter out the higher malignant tumor cells. The Jain and Kerbel study, an appropriate amount of angiogenesis inhibitors can make the blood vessels of the tumor cells tends to be "normalized" to improve the blood supply and oxygen, which will also help full access to chemotherapy drugs and tumor cells, to achieve a better therapeutic effect. Conventional radiotherapy, chemotherapy application, as an integral part of the comprehensive treatment of the tumor, will be the direction of the development of angiogenesis inhibitors. The one hand, angiogenesis inhibitors have the potential to improve the efficacy of radiotherapy, on the other hand received traditional treatment in patients with tumor regression period, the application of angiogenesis inhibitors may micrometastases in a resting state, thereby inhibiting tumor metastasis and recurrence.
Cell cycle control agent
The cell cycle is the basic process of cellular activities, the evolutionary process of cell development and the establishment of a more complex and sophisticated control mechanisms to ensure strict and orderly cell cycle alternately and each phase is sequentially changed. Cyclin-dependent kinase (CDK) is the core of the regulatory network of leading cycle start, and results. Cell cycle regulatory proteins (cyclin) positively regulates CDK, cyclin-dependent kinase inhibitor (CKI) from the negative regulatory role. Studies have shown that in a variety of tumor occurrence and development of CDK / cyclin overexpression or endogenous inhibitors, such as the decline in p16 expression or the pRb gene mutations, CDK activity can lead to loss of control, uncontrolled growth . CDK key role in the cell cycle caused by the development block cell cycle progression and induction of growth arrest-specific kinase inhibitor CDK inhibitors have a strong interest.
CDK regulation of key DNA integrity control monitoring points (CHK). When DNA damage, cell arrest in the G1 phase, S or G2 phase, to provide sufficient time to repair DNA. Anticancer drugs by breaking DNA, destruction of tumor cells while also activates chk, there is a small part of the tumor cells in drug-induced cycle arrest after repair system is able to activate and continue to survive, thereby reducing the efficacy of the drug. People trying to weaken tumor cells chk enhance normal cell chk role to improve the effect of chemotherapy. Such as more than 50% of tumor cells in the presence of a p53 mutation or deletion, lack G1 phase CHK advantage of this feature, the cell cycle can be modified, the specific design of the treatment, so that normal cells blocked in G1 phase, in order to improve the S phase-specific selective killing effect of the drug on tumor cells.
The present study is more cell cycle control agent flavopiridol and UCN-01. The U.S. National Cancer Institute (NCI) screened flavopiridolf261 is derived from a plant flavonoids, can compete with ATP binding sites, broad-spectrum inhibition of CDK role, including CDK1, 2, 4, 6, 7, also blocking the cell cycle in G1 and G2 phase, inhibit the activity of a variety of solid tumor cell proliferation. Flavopiridol with paclitaxel, gemcitabine, cisplatin in combination synergies, these chemotherapy drugs can inhibit the synthesis of DNA, the cells effectively concentrated in the S phase, can be the Flavopiridol mediated CDK inhibition improve their cells. cytotoxicity.
Epilogue
Very hot topic in the past two years, medical oncology community is the problem of multi-target drugs and combination therapy. The complex mechanism of the formation of solid tumors, the tumor tissue may be derived from a single gene mutation, but its growth potential new mutations, the course of treatment will produce drug resistance and effective method is the same time more than one key exception the joint intervention of the gene, so that not only can improve the therapeutic effect and to reduce the molecular resist the formation of dangerous clinical efficacy of sunitinib, sorafenib, is proof of this theory; another effective strategy is combination therapy, including targeted drug in combination with chemotherapy drugs, targeted drugs have a synergistic effect. The van Cruijsen pointed out that the inhibition of VEGF (R) and EGF (R) pathway, to avoid the potential for enhanced resistance to EGFR inhibitors of angiogenesis, can also make the anti-angiogenic effect is more significant. The superiority of the cell cycle inhibitor drugs in combination with cytotoxic drugs have been explained in the text. Of course, these theories are only a preliminary study the clinical needs deeper study and long-term observation, such as regimen is sequential administration or administration at the same time better, the order of administration, optimal dose and side effects comprehensive research, will have a convincing judgment.
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