Two ligand oligopeptides GV1 and GV2 were designed according to the putative binding region of VEGF to its receptors. GV1, GV2 and endosome releasing oligopeptide HA20 were conjugated with poly-L-lysine or protamine a...Two ligand oligopeptides GV1 and GV2 were designed according to the putative binding region of VEGF to its receptors. GV1, GV2 and endosome releasing oligopeptide HA20 were conjugated with poly-L-lysine or protamine and the resulting conjugates could interact with DNA in a noncovalent bond to form a complex. Using pSV2-β-galactosidase as a reporter gene, it has been demonstrated that exogenous gene was transferred into bovine aortic arch-derived endothelial cells (ABAE) andhuman malignant melanoma cell lines (A375) in vitro. In vivo experiments, exogenous gene was transferred into tumor vascular endothelial cells and tumor cells of subcutaneously transplanted human colon cancer LOVO, human malignant melanoma A375 and human hepatoma graft in nude mice. This system could also target gene to intrahepatically transplanted human hepatoma injected via portal vein in nude mice. These results are correlated with theGene delivery system targeting VEGF receptors relevant receptors (flt-1, flk-1/KDR) expression on the targeted cells and tissues.展开更多
To investigate the efficiency of suicide gene systems on vascular cells, HSV-tk/GCV and EC-CD/5-FC systems were established on vascular endothelial cells in vitro by retroviral transduction. Both modified cell lines w...To investigate the efficiency of suicide gene systems on vascular cells, HSV-tk/GCV and EC-CD/5-FC systems were established on vascular endothelial cells in vitro by retroviral transduction. Both modified cell lines were highly sensitive to prodrugs, the IC50 for GCV was less than 0.4 μM, and IC50 for 5-FC was less than 75 μM,while the parental endothelial cells were insensitive even at the highest concentrations of prodrugs in this experiment. Mixed cellular assay showed that significant bystander effect was exhibited in modified endothelial cells.When only 10% or 30% of the mixed cells were tk positive and exposed to 20 μM GCV for 6 days, more than 60% or 90% of the whole population was killed. Similar result was also found in CD positive cells. These results indicated that both HSV-tk/GCV and EC-CD/5-FC systems could efficiently suppress endothelial cell growth in vitro.展开更多
Treatment with bevacizumab,an antiangiogenic agent,in patients with metastatic or unresectable colorectal cancer was approved less than 4 years ago in Japan.Bevacizumab improves the survival of patients with metastati...Treatment with bevacizumab,an antiangiogenic agent,in patients with metastatic or unresectable colorectal cancer was approved less than 4 years ago in Japan.Bevacizumab improves the survival of patients with metastatic colorectal cancer;however,it may lead to complications such as bleeding,which are sometimes fatal.Bevacizumab should be administered only after careful consideration because the potential risks of therapy outweigh its benefits.Therefore,pharma-ceutical companies do not recommend bevacizumab therapy for patients with brain metastases.While some reports support the cautious use of bevacizumab,others report that it is not always necessary to prohibit its use in patients with metastases to the central nervous system(CNS),including the brain.Thus,bevacizumab therapy in colorectal cancer patients with brain metastases is controversial,and it is unclear whether brainmetastases are a risk factor for intracranial hemor-rhage during anti-vascular endothelial growth factor(VEGF)therapy.We report a 64-year-old man and a 65-year-old man with recurrent colorectal cancer with-out brain metastases;these patients developed multifocal and solitary intracranial hemorrhage,respectively,after the administration of bevacizumab.Our findings suggest that intracranial hemorrhage can occur even if the patient does not have brain metastases prior to bevacizumab treatment and also suggest that brain metastases are not a risk factor for intracranial hemor-rhage with bevacizumab treatment.These findings also question the necessity of excluding patients with brain metastases from clinical trials on anti-VEGF therapy.展开更多
文摘Two ligand oligopeptides GV1 and GV2 were designed according to the putative binding region of VEGF to its receptors. GV1, GV2 and endosome releasing oligopeptide HA20 were conjugated with poly-L-lysine or protamine and the resulting conjugates could interact with DNA in a noncovalent bond to form a complex. Using pSV2-β-galactosidase as a reporter gene, it has been demonstrated that exogenous gene was transferred into bovine aortic arch-derived endothelial cells (ABAE) andhuman malignant melanoma cell lines (A375) in vitro. In vivo experiments, exogenous gene was transferred into tumor vascular endothelial cells and tumor cells of subcutaneously transplanted human colon cancer LOVO, human malignant melanoma A375 and human hepatoma graft in nude mice. This system could also target gene to intrahepatically transplanted human hepatoma injected via portal vein in nude mice. These results are correlated with theGene delivery system targeting VEGF receptors relevant receptors (flt-1, flk-1/KDR) expression on the targeted cells and tissues.
文摘To investigate the efficiency of suicide gene systems on vascular cells, HSV-tk/GCV and EC-CD/5-FC systems were established on vascular endothelial cells in vitro by retroviral transduction. Both modified cell lines were highly sensitive to prodrugs, the IC50 for GCV was less than 0.4 μM, and IC50 for 5-FC was less than 75 μM,while the parental endothelial cells were insensitive even at the highest concentrations of prodrugs in this experiment. Mixed cellular assay showed that significant bystander effect was exhibited in modified endothelial cells.When only 10% or 30% of the mixed cells were tk positive and exposed to 20 μM GCV for 6 days, more than 60% or 90% of the whole population was killed. Similar result was also found in CD positive cells. These results indicated that both HSV-tk/GCV and EC-CD/5-FC systems could efficiently suppress endothelial cell growth in vitro.
文摘Treatment with bevacizumab,an antiangiogenic agent,in patients with metastatic or unresectable colorectal cancer was approved less than 4 years ago in Japan.Bevacizumab improves the survival of patients with metastatic colorectal cancer;however,it may lead to complications such as bleeding,which are sometimes fatal.Bevacizumab should be administered only after careful consideration because the potential risks of therapy outweigh its benefits.Therefore,pharma-ceutical companies do not recommend bevacizumab therapy for patients with brain metastases.While some reports support the cautious use of bevacizumab,others report that it is not always necessary to prohibit its use in patients with metastases to the central nervous system(CNS),including the brain.Thus,bevacizumab therapy in colorectal cancer patients with brain metastases is controversial,and it is unclear whether brainmetastases are a risk factor for intracranial hemor-rhage during anti-vascular endothelial growth factor(VEGF)therapy.We report a 64-year-old man and a 65-year-old man with recurrent colorectal cancer with-out brain metastases;these patients developed multifocal and solitary intracranial hemorrhage,respectively,after the administration of bevacizumab.Our findings suggest that intracranial hemorrhage can occur even if the patient does not have brain metastases prior to bevacizumab treatment and also suggest that brain metastases are not a risk factor for intracranial hemor-rhage with bevacizumab treatment.These findings also question the necessity of excluding patients with brain metastases from clinical trials on anti-VEGF therapy.
