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Kumaravel Somasundaram - One of the best experts on this subject based on the ideXlab platform.
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p73|[beta]|-expressing recombinant adenovirus: a potential anticancer Agent
Cancer Gene Therapy, 2005Co-Authors: Sanjeev Das, Srikanth Nama, Sini Antony, Kumaravel SomasundaramAbstract:Tumor suppressor p53-based Gene Therapy strategy is ineffective in certain conditions. p73, a p53 homologue, could be a potential alternative Gene Therapy Agent as it has been found to be an important determinant of chemosensitivity in cancer cells. Previously, we have reported the Generation of a replication-deficient adenovirus expressing p73 $\beta$ (Ad-p73). In this study, we evaluated the therapeutic potential of Ad-p73 against a panel of cancer cells (n=12) of different tissue origin. Ad-p73 infected all the cell lines tested very efficiently resulting in several-fold increase in p73 $\beta$ levels, which is also functional as it activated the known target Gene $p21^W^A^F^1^/^C^I^P^1$. Infection with Ad-p73 resulted in potent cytotoxicity in all the cell lines tested. The mechanism of p73-induced cytotoxicity in these cell lines is found to be due to a combination of cell cycle arrest and induction of apoptosis. In addition, exogenous overexpression of p73 by Ad-p73 infection increased the chemosensitivity of cancer cells by many fold to commonly used drug adriamycin. Moreover, Ad-p73 is more efficient than Ad-p53 in enhancing the chemosensitivity of mutant p53 harboring cells. Furthermore, Ad-p73 infection did not induce apoptosis in human normal lung fibroblasts (HEL 299) and human immortalized keratinocytes (HaCaT). These results suggest that Ad-p73 is a potent cytotoxic Agent specifically against cancer cells and could be developed as a cancer Gene Therapy Agent either alone or in combination with chemotherapeutic Agents.
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Efficient growth inhibition of HPV 16 E6-expressing cells by an adenovirus-expressing p53 homologue p73β
Oncogene, 2003Co-Authors: Sanjeev Das, Wafik S El-deiry, Kumaravel SomasundaramAbstract:Tumor suppressor p53 functions are downregulated in most cervical cancers, because the product of human papilloma virus (HPV) oncoGene E6 binds to and inactivates p53 by promoting its degradation. p73, a p53 homologue, is similar to p53 in structure and function but yet not degraded by HPV E6 Gene product. In this study, we have developed a replication-deficient recombinant adenovirus, which expresses p73 β (Ad-p73). Infection of human cancer cells with Ad-p73 results in several fold increase of p73 β levels as well as its known target Genes like p21^WAF1/CIP1. Ad-p73-infected cells showed reduced cellular DNA synthesis, arrest in G1 phase of cell cycle and induction of apoptosis. Ad-p73 inhibited the growth of cancer cells of different types. More importantly, Ad-p73 inhibited the growth of cell lines carrying HPV E6 Gene, which was introduced by stable integration, more efficiently in comparison to an Ad-p53. Furthermore, Ad-p73 also inhibited the growth of HeLa cells, a cell line derived from cervical cancer, very efficiently. The ability of Ad-p73 to inhibit the growth of HPV E6-expressing cells and HeLa cells correlated with the stable expression of functional p73 in the presence of E6. These results suggest that Ad-p73 could be used as a potential Gene Therapy Agent against cervical cancer.
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Efficient growth inhibition of HPV 16 E6-expressing cells by an adenovirus-expressing p53 homologue p73β
Oncogene, 2003Co-Authors: Sanjeev Das, Wafik S El-deiry, Kumaravel SomasundaramAbstract:Tumor suppressor p53 functions are downregulated in most cervical cancers, because the product of human papilloma virus (HPV) oncoGene E6 binds to and inactivates p53 by promoting its degradation. p73, a p53 homologue, is similar to p53 in structure and function but yet not degraded by HPV E6 Gene product. In this study, we have developed a replication-deficient recombinant adenovirus, which expresses p73 \beta (Ad-p73). Infection of human cancer cells with Ad-p73 results in several fold increase of p73 \beta levels as well as its known target Genes like $p21^{WAF1/CIP1}$. Ad-p73-infected cells showed reduced cellular DNA synthesis, arrest in G1 phase of cell cycle and induction of apoptosis. Ad-p73 inhibited the growth of cancer cells of different types. More importantly, Ad-p73 inhibited the growth of cell lines carrying HPV E6 Gene, which was introduced by stable integration, more efficiently in comparison to an Ad-p53. Furthermore, Ad-p73 also inhibited the growth of HeLa cells, a cell line derived from cervical cancer, very efficiently. The ability of Ad-p73 to inhibit the growth of HPV E6-expressing cells and HeLa cells correlated with the stable expression of functional p73 in the presence of E6. These results suggest that Ad-p73 could be used as a potential Gene Therapy Agent against cervical cancer.
Kirk H Hammond - One of the best experts on this subject based on the ideXlab platform.
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angiogenic Gene Therapy Agent trial in patients with stable angina pectoris
Circulation, 2002Co-Authors: Cindy L. Grines, Matthew W. Watkins, Greg Helmer, William F. Penny, Jeffrey A. Brinker, Jonathan D. Marmur, Andrew West, Jeffery J. Rade, Pran Marrott, Kirk H HammondAbstract:Background— The angiogenic response to myocardial ischemia can be augmented in animal models by Gene transfer with the use of a replication defective adenovirus (Ad) containing a human fibroblast growth factor (FGF) Gene. Methods and Results— The objectives of the Angiogenic Gene Therapy (Agent) trial were to evaluate the safety and anti-ischemic effects of 5 ascending doses of Ad5-FGF4 in patients with angina and to select potentially safe and effective doses for subsequent study. Seventy-nine patients with chronic stable angina Canadian Cardiovascular Society class 2 or 3 underwent double-blind randomization (1:3) to placebo (n=19) or Ad5-FGF4 (n=60). Safety evaluations were performed at each visit and exercise treadmill testing (ETT) at baseline and at 4 and 12 weeks. Single intracoronary administration of Ad5-FGF4 seemed to be safe and well tolerated with no immediate adverse events. Fever of <1-day duration occurred in 3 patients in the highest-dose group. Transient, asymptomatic elevations in liver ...
Sanjeev Das - One of the best experts on this subject based on the ideXlab platform.
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p73|[beta]|-expressing recombinant adenovirus: a potential anticancer Agent
Cancer Gene Therapy, 2005Co-Authors: Sanjeev Das, Srikanth Nama, Sini Antony, Kumaravel SomasundaramAbstract:Tumor suppressor p53-based Gene Therapy strategy is ineffective in certain conditions. p73, a p53 homologue, could be a potential alternative Gene Therapy Agent as it has been found to be an important determinant of chemosensitivity in cancer cells. Previously, we have reported the Generation of a replication-deficient adenovirus expressing p73 $\beta$ (Ad-p73). In this study, we evaluated the therapeutic potential of Ad-p73 against a panel of cancer cells (n=12) of different tissue origin. Ad-p73 infected all the cell lines tested very efficiently resulting in several-fold increase in p73 $\beta$ levels, which is also functional as it activated the known target Gene $p21^W^A^F^1^/^C^I^P^1$. Infection with Ad-p73 resulted in potent cytotoxicity in all the cell lines tested. The mechanism of p73-induced cytotoxicity in these cell lines is found to be due to a combination of cell cycle arrest and induction of apoptosis. In addition, exogenous overexpression of p73 by Ad-p73 infection increased the chemosensitivity of cancer cells by many fold to commonly used drug adriamycin. Moreover, Ad-p73 is more efficient than Ad-p53 in enhancing the chemosensitivity of mutant p53 harboring cells. Furthermore, Ad-p73 infection did not induce apoptosis in human normal lung fibroblasts (HEL 299) and human immortalized keratinocytes (HaCaT). These results suggest that Ad-p73 is a potent cytotoxic Agent specifically against cancer cells and could be developed as a cancer Gene Therapy Agent either alone or in combination with chemotherapeutic Agents.
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Efficient growth inhibition of HPV 16 E6-expressing cells by an adenovirus-expressing p53 homologue p73β
Oncogene, 2003Co-Authors: Sanjeev Das, Wafik S El-deiry, Kumaravel SomasundaramAbstract:Tumor suppressor p53 functions are downregulated in most cervical cancers, because the product of human papilloma virus (HPV) oncoGene E6 binds to and inactivates p53 by promoting its degradation. p73, a p53 homologue, is similar to p53 in structure and function but yet not degraded by HPV E6 Gene product. In this study, we have developed a replication-deficient recombinant adenovirus, which expresses p73 β (Ad-p73). Infection of human cancer cells with Ad-p73 results in several fold increase of p73 β levels as well as its known target Genes like p21^WAF1/CIP1. Ad-p73-infected cells showed reduced cellular DNA synthesis, arrest in G1 phase of cell cycle and induction of apoptosis. Ad-p73 inhibited the growth of cancer cells of different types. More importantly, Ad-p73 inhibited the growth of cell lines carrying HPV E6 Gene, which was introduced by stable integration, more efficiently in comparison to an Ad-p53. Furthermore, Ad-p73 also inhibited the growth of HeLa cells, a cell line derived from cervical cancer, very efficiently. The ability of Ad-p73 to inhibit the growth of HPV E6-expressing cells and HeLa cells correlated with the stable expression of functional p73 in the presence of E6. These results suggest that Ad-p73 could be used as a potential Gene Therapy Agent against cervical cancer.
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Efficient growth inhibition of HPV 16 E6-expressing cells by an adenovirus-expressing p53 homologue p73β
Oncogene, 2003Co-Authors: Sanjeev Das, Wafik S El-deiry, Kumaravel SomasundaramAbstract:Tumor suppressor p53 functions are downregulated in most cervical cancers, because the product of human papilloma virus (HPV) oncoGene E6 binds to and inactivates p53 by promoting its degradation. p73, a p53 homologue, is similar to p53 in structure and function but yet not degraded by HPV E6 Gene product. In this study, we have developed a replication-deficient recombinant adenovirus, which expresses p73 \beta (Ad-p73). Infection of human cancer cells with Ad-p73 results in several fold increase of p73 \beta levels as well as its known target Genes like $p21^{WAF1/CIP1}$. Ad-p73-infected cells showed reduced cellular DNA synthesis, arrest in G1 phase of cell cycle and induction of apoptosis. Ad-p73 inhibited the growth of cancer cells of different types. More importantly, Ad-p73 inhibited the growth of cell lines carrying HPV E6 Gene, which was introduced by stable integration, more efficiently in comparison to an Ad-p53. Furthermore, Ad-p73 also inhibited the growth of HeLa cells, a cell line derived from cervical cancer, very efficiently. The ability of Ad-p73 to inhibit the growth of HPV E6-expressing cells and HeLa cells correlated with the stable expression of functional p73 in the presence of E6. These results suggest that Ad-p73 could be used as a potential Gene Therapy Agent against cervical cancer.
Cindy L. Grines - One of the best experts on this subject based on the ideXlab platform.
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Angiogenic Gene Therapy (Agent) Trial in Patients With Stable Angina Pectoris
Circulation, 2002Co-Authors: Cindy L. Grines, Matthew W. Watkins, Greg Helmer, William F. Penny, Jeffrey A. Brinker, Jonathan D. Marmur, Andrew West, Jeffery J. Rade, Pran Marrott, H. Kirk HammondAbstract:Background— The angiogenic response to myocardial ischemia can be augmented in animal models by Gene transfer with the use of a replication defective adenovirus (Ad) containing a human fibroblast growth factor (FGF) Gene. Methods and Results— The objectives of the Angiogenic Gene Therapy (Agent) trial were to evaluate the safety and anti-ischemic effects of 5 ascending doses of Ad5-FGF4 in patients with angina and to select potentially safe and effective doses for subsequent study. Seventy-nine patients with chronic stable angina Canadian Cardiovascular Society class 2 or 3 underwent double-blind randomization (1:3) to placebo (n=19) or Ad5-FGF4 (n=60). Safety evaluations were performed at each visit and exercise treadmill testing (ETT) at baseline and at 4 and 12 weeks. Single intracoronary administration of Ad5-FGF4 seemed to be safe and well tolerated with no immediate adverse events. Fever of
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angiogenic Gene Therapy Agent trial in patients with stable angina pectoris
Circulation, 2002Co-Authors: Cindy L. Grines, Matthew W. Watkins, Greg Helmer, William F. Penny, Jeffrey A. Brinker, Jonathan D. Marmur, Andrew West, Jeffery J. Rade, Pran Marrott, Kirk H HammondAbstract:Background— The angiogenic response to myocardial ischemia can be augmented in animal models by Gene transfer with the use of a replication defective adenovirus (Ad) containing a human fibroblast growth factor (FGF) Gene. Methods and Results— The objectives of the Angiogenic Gene Therapy (Agent) trial were to evaluate the safety and anti-ischemic effects of 5 ascending doses of Ad5-FGF4 in patients with angina and to select potentially safe and effective doses for subsequent study. Seventy-nine patients with chronic stable angina Canadian Cardiovascular Society class 2 or 3 underwent double-blind randomization (1:3) to placebo (n=19) or Ad5-FGF4 (n=60). Safety evaluations were performed at each visit and exercise treadmill testing (ETT) at baseline and at 4 and 12 weeks. Single intracoronary administration of Ad5-FGF4 seemed to be safe and well tolerated with no immediate adverse events. Fever of <1-day duration occurred in 3 patients in the highest-dose group. Transient, asymptomatic elevations in liver ...
K W Southern - One of the best experts on this subject based on the ideXlab platform.
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Topical cystic fibrosis transmembrane conductance regulator Gene replacement for cystic fibrosis-related lung disease.
The Cochrane database of systematic reviews, 2013Co-Authors: Tim W R Lee, K W SouthernAbstract:Cystic fibrosis is caused by a defective Gene encoding a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), and is characterised by chronic lung infection resulting in inflammation and progressive lung damage that results in a reduced life expectancy. To determine whether topical CFTR Gene replacement Therapy to the lungs in people with cystic fibrosis is associated with improvements in clinical outcomes, and to assess any adverse effects. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings.Date of most recent search: 22 August 2013.An additional search of the National Institutes for Health (NIH) Genetic Modification Clinical Research Information System (GeMCRIS) was also performed for the years 1992 to 2013.Date of most recent search: 04 September 2013. Randomised controlled trials comparing topical CFTR Gene delivery to the lung, using either viral or non-viral delivery systems, with placebo or an alternative delivery system in people with confirmed cystic fibrosis. The authors independently extracted data and assessed study quality. Authors of included studies were contacted and asked for any available additional data. Meta-analysis was limited due to differing study designs. Three randomised controlled trials met the inclusion criteria for this review, involving a total of 155 participants. Fourteen studies were excluded. The included studies differed in terms of CFTR Gene replacement Agent and study design, which limited the meta-analysis.Although the first Moss study reported a significant improvement in respiratory function (forced expiratory volume at one second) 30 days after participants had received their first dose of Gene Therapy Agent, this finding was not confirmed in their larger second study or in our meta-analysis.In participants who received the CFTR Gene transfer Agents in the Alton study, "influenza-like" symptoms were found (risk ratio 7.00 (95% confidence interval 1.10 to 44.61)). There were no other significant increases in adverse events in any of the studies.Alton measured ion transport in the lower airways and demonstrated significant changes toward normal values in the participants who received Gene transfer Agents (P < 0.0001), mean difference 6.86 (95% confidence interval 3.77 to 9.95). In these participants there was also evidence of increased salt transport in cells obtained by brushing the lower airway. These outcomes, whilst important, are not of direct clinical relevance. There is currently no evidence to support the use of CFTR Gene transfer Agents as a treatment for lung disease in people with cystic fibrosis. Future studies need to investigate clinically important outcome measures.
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Topical cystic fibrosis transmembrane conductance regulator Gene replacement for cystic fibrosis-related lung disease.
The Cochrane database of systematic reviews, 2012Co-Authors: Tim W R Lee, K W SouthernAbstract:Cystic fibrosis is caused by a defective Gene encoding a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), and is characterised by chronic lung infection resulting in inflammation and progressive lung damage that results in a reduced life expectancy. To determine whether topical CFTR Gene replacement Therapy to the lungs in people with cystic fibrosis is associated with improvements in clinical outcomes, and to assess any adverse effects. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings.Date of most recent search: 19 July 2012.An additional search of the National Institutes for Health (NIH) Genetic Modification Clinical Research Information System (GeMCRIS) was also performed for the years 1992 to 2012.Date of most recent search: 25 July 2012. Randomised controlled trials comparing topical CFTR Gene delivery to the lung, using either viral or non-viral delivery systems, with placebo or an alternative delivery system in people with confirmed cystic fibrosis. The authors independently extracted data and assessed study quality. Authors of included studies were contacted and asked for any available additional data. Meta-analysis was limited due to differing study designs. Three randomised controlled trials met the inclusion criteria for this review, involving a total of 155 participants. Fourteen studies were excluded. The included studies differed in terms of CFTR Gene replacement Agent and study design, which limited the meta-analysis.Although the first Moss study reported a significant improvement in respiratory function (forced expiratory volume at one second) 30 days after participants had received their first dose of Gene Therapy Agent, this finding was not confirmed in their larger second study or in our meta-analysis.In participants who received the CFTR Gene transfer Agents in the Alton study, "influenza-like" symptoms were found (risk ratio 7.00 (95% confidence interval 1.10 to 44.61)). There were no other significant increases in adverse events in any of the studies.Alton measured ion transport in the lower airways and demonstrated significant changes toward normal values in the participants who received Gene transfer Agents (P < 0.0001), mean difference 6.86 (95% CI of 3.77 to 9.95). In these participants there was also evidence of increased salt transport in cells obtained by brushing the lower airway. These outcomes, whilst important, are not of direct clinical relevance. There is currently no evidence to support the use of CFTR Gene transfer reAgents as a treatment for lung disease in people with cystic fibrosis. Future studies need to investigate clinically important outcome measures.
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Topical cystic fibrosis transmembrane conductance regulator Gene replacement for cystic fibrosis-related lung disease.
The Cochrane database of systematic reviews, 2007Co-Authors: T Lee, K W SouthernAbstract:Cystic fibrosis is caused by a defective Gene encoding a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), and is characterised by chronic lung infection resulting in inflammation and progressive lung damage that results in a reduced life expectancy. To determine whether topical CFTR Gene replacement Therapy to the lungs in people with cystic fibrosis is associated with improvements in clinical outcomes, and to assess any adverse effects. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. Date of most recent search: February 2007 Randomised controlled trials comparing topical CFTR Gene delivery to the lung, using either viral or non-viral delivery systems, with placebo or an alternative delivery system in people with confirmed cystic fibrosis. The authors independently extracted data and assessed study quality. Authors of included studies were contacted and asked for any available additional data. Meta-analysis was limited due to differing study designs. Three randomised controlled trials met the inclusion criteria for this review, involving a total of 155 participants. Thirteen studies were excluded. The included studies differed in terms of CFTR Gene replacement Agent and study design, which limited the meta-analysis. Although the first Moss study reported a significant improvement in respiratory function (FEV(1)) 30 days after participants had received their first dose of Gene Therapy Agent, this finding was not confirmed in their larger second study or in our meta-analysis.In participants who received the CFTR Gene transfer Agents in the Alton study, "influenza-like" symptoms were found (relative risk 7.00 (95% confidence interval (CI) 1.10 to 44.61)). There were no other significant increases in adverse events in any of the studies. Alton measured ion transport in the lower airways and demonstrated significant changes toward normal values in the participants who received Gene transfer Agents (P < 0.0001), weighted mean difference 6.86 (95% CI of 3.77 to 9.95). In these participants there was also evidence of increased salt transport in cells obtained by brushing the lower airway. These outcomes, whilst important, are not of direct clinical relevance. There is currently no evidence to support the use of CFTR Gene transfer reAgents as a treatment for lung disease in people with cystic fibrosis. Future studies need to investigate clinically important outcome measures.