Cerebral hemisphere gliomas occurring approximately 51.4% of all gliomas, to a maximum of astrocytoma; followed glioblastoma tumors and oligodendrogliomas. Ventricular system is more occurrence site glioma, accounting for 23.9% of the total number of glioma, mainly for ependymoma, medulloblastoma, astrocytoma, cerebellar gliomas account for 13% of the total number of glioma, mainly astrocytoma. The main clinical manifestations of malignant gliomas as headache, nausea, vomiting and visual disturbances. Others include seizures, dizziness, abducens nerve palsy and behavioral and personality changes and so on.
Traditional treatment of choice
Traditionally, chemotherapy drugs of choice for malignant brain tumors is nitrosourea, such as carmustine (BCNU) and lomustine (CCNU). Non-ionic character and high lipid solubility makes it easy to penetrate the blood-brain barrier.
Carmustine (BCNU) is the most widely used chemotherapeutic agents in brain tumors, with a fat-soluble and low molecular weight, through the blood-brain barrier in vivo decomposition of the two active ingredients, having a carbamoyl activity of A as alkylating agent. It causes the DNA guanine 6 oxygen atoms alkylated. Q causes DNA chain crosslinking affect DNA replication, killing tumor cells: both more binding sites, the topical administration to achieve higher concentrations it easy to play the role of intravenous administration of carmustine short plasma half-life. Accumulation can occur when doses greater than 1400mg a series of serious complications. Including delayed inhibition of hematopoiesis, liver toxicity and pulmonary fibrosis f21. To solve these problems, many scholars on the mode of administration of carmustine and means a lot of useful exploration in order to improve the effect of chemotherapy, improve patient quality of life. The study found that sustained-release formulations can significantly reduce carmustine (BCNU) side effects, and prolong survival.
Oral formulations temozolomide
Temozolomide is currently the only FDA-approved for the treatment of malignant gliomas oral chemotherapy. Temozolomide (Temozolomide, TMZ) belong to the second generation of alkylating chemotherapy drugs. It can be directly on the substrate DNA synthesis, so that the methylation, which causes DNA single-strand and double-strand breaks, inhibition of DNA replication, leading to cell death. Because the molecule is small, has good lipophilic, so TMZ can better blood-brain barrier in the central nervous system can achieve plasma concentrations of 40%, thus making the treatment of tumors in the central nervous system, there is a good prospect . 1999 FDA approval of TMZ for recurrent malignant astrocytoma chemotherapy. March 2005, FDA approved for the treatment of new brain glioblastoma patients. In Europe, TMZ is approved for recurrent malignant astrocytoma and glioblastoma. "New England Journal of Medicine," the commentary, with national experts "to create a new era of brain tumor chemotherapy", "brain tumor chemotherapy milestone" and described as temozolomide.
According to data provided by the network m, 2010 Temozolomide domestic market share has reached 60 million yuan, compared with 2009, an increase of 50%. From 2008 to 2010, nearly three years of sales data, the domestic temozolomide relative to the average annual growth rate of around 40%. Temozolomide the major manufacturers in Tianjin Tasly Pharmaceutical, 芬兰奥利安 Pharmaceuticals and Schering-Plough Pharmaceuticals. In 2010 the three companies temozolomide domestic market share was 52.75%, 35.81%and 11.44%.
Antiangiogenic therapy
Studies have shown that malignant glioma is a highly vascularized solid tumors, malignant gliomas in recent years, foreign scholars antiangiogenic therapy made many attempts, including thalidomide and bevacizumab. Which the United States Brain Tumor Center at Duke University completed a bevacizumab plus irinotecan (iri notecan, CPT-11) treatment of recurrent malignant glioma Phase Ⅱ clinical research data are encouraging, the overall objective response rate was 63 %, the median PFS was 23 weeks, 6 months PFS rates in grade Ⅳ and Ⅲ grade gliomas were 30% and 56%, median overall survival was 40 weeks. Based on results of this study, 2009 U.S. NCCN Clinical Practice Guidelines in Oncology recommend bevacizumab alone or in combination with CPT-11 program as a recurrent high-grade glioma is one of the salvage regimen.
2009 FDA approval of bevacizumab (Avastin) in the conventional treatment for the condition continued to deteriorate under the conditions of glioblastoma multiforme (glioblastoma multiforme, GBM) patients.
Investigational drugs
Currently in clinical glioma drugs include: molecular targets for monoclonal antibodies such as bevacizumab and cetuximab; EGFR tyrosine kinase inhibitors and VEGF tyrosine kinase inhibitors such as Cediranib and Lapatinib, as well as serine - threonine kinase inhibitor Enzastaurin, integrin antagonists Cilengitide (Cilengitide) and so on.
Enzastaurin EU and FDA approved in 2006 Enzastaurin as pleomorphic glioblastoma rare disease drug. This medicine is used recurrent pleomorphic glioblastoma Phase Ⅱ trial results have been published in the American Society of Clinical Oncology. Enrolled 92 patients, the use of 500mg a day after Enzastaurin response rate of 20 to 25%. Enzastaurin well tolerated, the most common side effects are reduced platelets. Enzastaurin can inhibit tumor cell growth, survival and angiogenesis. It does this by inhibiting PKC-B and PI3 kinase / AKT pathway and reduce cancer cell survival. Phase Ⅲ clinical drug studies are in progress.
Cilengitide in pleomorphic glioblastoma (GBM) patients with newly diagnosed stage Ⅱ conducted an independent study shows Cilengitide combined chemoradiotherapy (concomitant and adjuvant temozolomide plus radiotherapy) may prolong survival. Cilengitide as the first integrin inhibitor anticancer drugs, has entered Phase Ⅲ clinical development. It targeted to the tumor and the tumor with nutrients, and promote the growth of cancer cells in the blood supply structure.
Cilengitide Phase Ⅱ clinical study's primary endpoint showed Cilengitide 2000mg treatment group are higher than the 500mg group overall survival trend. The median survival time was 18.9 months (95% CI16.6-21.9), 12-month follow-up, overall survival was 79.5% (95% CI71-87).
Merck Oncology Group executive vice president, said Dr. Wolfgang Wein Cilengitide treat this devastating disease with possibilities.
Studies have shown that malignant glioma is a highly vascularized solid tumors, malignant gliomas in recent years, foreign scholars antiangiogenic therapy made many attempts, including thalidomide and bevacizumab. Which the United States Brain Tumor Center at Duke University completed a bevacizumab plus irinotecan (iri notecan, CPT-11) treatment of recurrent malignant glioma Phase Ⅱ clinical research data are encouraging, the overall objective response rate was 63 %, the median PFS was 23 weeks, 6 months PFS rates in grade Ⅳ and Ⅲ grade gliomas were 30% and 56%, median overall survival was 40 weeks. Based on results of this study, 2009 U.S. NCCN Clinical Practice Guidelines in Oncology recommend bevacizumab alone or in combination with CPT-11 program as a recurrent high-grade glioma is one of the salvage regimen.
2009 FDA approval of bevacizumab (Avastin) in the conventional treatment for the condition continued to deteriorate under the conditions of glioblastoma multiforme (glioblastoma multiforme, GBM) patients.
Investigational drugs
Currently in clinical glioma drugs include: molecular targets for monoclonal antibodies such as bevacizumab and cetuximab; EGFR tyrosine kinase inhibitors and VEGF tyrosine kinase inhibitors such as Cediranib and Lapatinib, as well as serine - threonine kinase inhibitor Enzastaurin, integrin antagonists Cilengitide (Cilengitide) and so on.
Enzastaurin EU and FDA approved in 2006 Enzastaurin as pleomorphic glioblastoma rare disease drug. This medicine is used recurrent pleomorphic glioblastoma Phase Ⅱ trial results have been published in the American Society of Clinical Oncology. Enrolled 92 patients, the use of 500mg a day after Enzastaurin response rate of 20 to 25%. Enzastaurin well tolerated, the most common side effects are reduced platelets. Enzastaurin can inhibit tumor cell growth, survival and angiogenesis. It does this by inhibiting PKC-B and PI3 kinase / AKT pathway and reduce cancer cell survival. Phase Ⅲ clinical drug studies are in progress.
Cilengitide in pleomorphic glioblastoma (GBM) patients with newly diagnosed stage Ⅱ conducted an independent study shows Cilengitide combined chemoradiotherapy (concomitant and adjuvant temozolomide plus radiotherapy) may prolong survival. Cilengitide as the first integrin inhibitor anticancer drugs, has entered Phase Ⅲ clinical development. It targeted to the tumor and the tumor with nutrients, and promote the growth of cancer cells in the blood supply structure.
Cilengitide Phase Ⅱ clinical study's primary endpoint showed Cilengitide 2000mg treatment group are higher than the 500mg group overall survival trend. The median survival time was 18.9 months (95% CI16.6-21.9), 12-month follow-up, overall survival was 79.5% (95% CI71-87).
Merck Oncology Group executive vice president, said Dr. Wolfgang Wein Cilengitide treat this devastating disease with possibilities.
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