Pub Date : 2008-11-03DOI: 10.2174/1874079000802010042
R. Mirzayans, D. Murray
Our genetic material is constantly damaged by internal sources such as reactive oxygen species and external sources such as ionizing radiation and sunlight. However, we seldom notice these injuries because our cells possess elegant DNA surveillance networks that serve to maintain cellular homeostasis. These networks are complex signal transduction pathways that coordinate cell cycle checkpoints and DNA repair processes to eliminate DNA damage, as well as invoking pathways such as sustained growth arrest (i.e., accelerated senescence) and apoptotic cell death to eliminate injured cells from the proliferating population. The p53 tumor suppressor protein and its downstream effector p21 are key regulators of these various responses. Failure of cells to properly activate p53/p21-mediated events following genotoxic stress may lead to the development of genomic instability and the emergence of malignant cells which exhibit stem cell-like properties. It is therefore not surprising that defects in major players of the DNA surveillance networks are the underlying cause for numerous debilitating human genetic disorders that are characterized by genomic instability, premature aging, and cancer proneness. In this article, we first provide an update on the role of the p53 signaling pathway in determining the fate of human cells following exposure to DNA-damaging agents. We next review the clinical and laboratory features of the most extensively studied human genome instability disorders including xeroderma pigmentosum, Cockayne syndrome, ataxia telangiectasia, and Li-Fraumeni syndrome, and discuss the current knowledge on the biological consequences of deregulated p53 signaling in cells derived from patients with such disorders.
{"title":"Human Genetic Disorders Associated with Genome Instability, Premature Aging and Cancer Predisposition","authors":"R. Mirzayans, D. Murray","doi":"10.2174/1874079000802010042","DOIUrl":"https://doi.org/10.2174/1874079000802010042","url":null,"abstract":"Our genetic material is constantly damaged by internal sources such as reactive oxygen species and external sources such as ionizing radiation and sunlight. However, we seldom notice these injuries because our cells possess elegant DNA surveillance networks that serve to maintain cellular homeostasis. These networks are complex signal transduction pathways that coordinate cell cycle checkpoints and DNA repair processes to eliminate DNA damage, as well as invoking pathways such as sustained growth arrest (i.e., accelerated senescence) and apoptotic cell death to eliminate injured cells from the proliferating population. The p53 tumor suppressor protein and its downstream effector p21 are key regulators of these various responses. Failure of cells to properly activate p53/p21-mediated events following genotoxic stress may lead to the development of genomic instability and the emergence of malignant cells which exhibit stem cell-like properties. It is therefore not surprising that defects in major players of the DNA surveillance networks are the underlying cause for numerous debilitating human genetic disorders that are characterized by genomic instability, premature aging, and cancer proneness. In this article, we first provide an update on the role of the p53 signaling pathway in determining the fate of human cells following exposure to DNA-damaging agents. We next review the clinical and laboratory features of the most extensively studied human genome instability disorders including xeroderma pigmentosum, Cockayne syndrome, ataxia telangiectasia, and Li-Fraumeni syndrome, and discuss the current knowledge on the biological consequences of deregulated p53 signaling in cells derived from patients with such disorders.","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"2 1","pages":"42-52"},"PeriodicalIF":0.0,"publicationDate":"2008-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68050639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-09-05DOI: 10.2174/1874079000802010025
S. Ingvarsson
Like other cancer types, breast cancer is considered to be a genetic disease. While the majority of genetic changes are somatic, a minority are in germline. About 10-20% of breast cancer is thought to be due to a germline mutation in high-penetrance genes, where the major focus has been on BRCA1 and BRCA2. Some of these mutations are defined as founder mutations. Studies on founder mutations yield important information, mainly due to a large number of available carriers with the same mutation, regarding penetrance, expression, genetic modifiers or low-penetrant genes and influence from the environment. Population studies are also valuable due the possibilities for evaluating clinicopathological data in a group of patients who have the same mutation. In Iceland a rare founder mutation has been detected in BRCA1, and a frequent founder mutation has been detected in BRCA2. In addition to population-based studies on genetics and clinicopathology, an extensive analysis of somatic changes in tumours of BRCA2 founder mutation carriers has been made.
{"title":"Population Approach in Breast Cancer Research Based on Integration of Genetic, Clinicopathological and Genealogical Clues","authors":"S. Ingvarsson","doi":"10.2174/1874079000802010025","DOIUrl":"https://doi.org/10.2174/1874079000802010025","url":null,"abstract":"Like other cancer types, breast cancer is considered to be a genetic disease. While the majority of genetic changes are somatic, a minority are in germline. About 10-20% of breast cancer is thought to be due to a germline mutation in high-penetrance genes, where the major focus has been on BRCA1 and BRCA2. Some of these mutations are defined as founder mutations. Studies on founder mutations yield important information, mainly due to a large number of available carriers with the same mutation, regarding penetrance, expression, genetic modifiers or low-penetrant genes and influence from the environment. Population studies are also valuable due the possibilities for evaluating clinicopathological data in a group of patients who have the same mutation. In Iceland a rare founder mutation has been detected in BRCA1, and a frequent founder mutation has been detected in BRCA2. In addition to population-based studies on genetics and clinicopathology, an extensive analysis of somatic changes in tumours of BRCA2 founder mutation carriers has been made.","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"2 1","pages":"25-30"},"PeriodicalIF":0.0,"publicationDate":"2008-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68051081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-09-05DOI: 10.2174/1874079000802010031
Chao Ma, Jiangbing Zhou, Xiaolu Yin, C. Jie, Dongming Xing, L. Du, Ying Zhang
Human lung cancer remains one of the deadliest diseases worldwide. New approaches are needed for improved lung cancer treatment. In this study, we found that M. tuberculosis culture supernatant (TB-SN) could inhibit human lung cancer cell proliferation through a caspase-dependent apoptosis pathway and induce cell cycle arrest in G1 phase. The active components responsible for the growth inhibitory activities were attributed to some proteins or protein complex with molecular weight more than 100 kD. These findings are significant and may provide new insight into a possible antagonism between M. tuberculosis and lung cancer and also have implications for development of an alternative approach for lung cancer treatment.
{"title":"Mycobacterium tuberculosis Culture Supernatant Induces Cancer Cell Apoptosis and Cell Cycle Arrest","authors":"Chao Ma, Jiangbing Zhou, Xiaolu Yin, C. Jie, Dongming Xing, L. Du, Ying Zhang","doi":"10.2174/1874079000802010031","DOIUrl":"https://doi.org/10.2174/1874079000802010031","url":null,"abstract":"Human lung cancer remains one of the deadliest diseases worldwide. New approaches are needed for improved lung cancer treatment. In this study, we found that M. tuberculosis culture supernatant (TB-SN) could inhibit human lung cancer cell proliferation through a caspase-dependent apoptosis pathway and induce cell cycle arrest in G1 phase. The active components responsible for the growth inhibitory activities were attributed to some proteins or protein complex with molecular weight more than 100 kD. These findings are significant and may provide new insight into a possible antagonism between M. tuberculosis and lung cancer and also have implications for development of an alternative approach for lung cancer treatment.","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"2 1","pages":"31-41"},"PeriodicalIF":0.0,"publicationDate":"2008-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68050588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-09-04DOI: 10.2174/1874079000802010015
A. Konur, A. Graser, I. Klamp, S. Kreiter, Abderraouf Selmi, M. Diken, C. Huber, Ö. Türeci, U. Şahin
As shown previously, encapsulation of a peptide derived from tyrosinase-related protein2 (TRP2) into liposomes (artificial virus envelope (AVE) 3) resulted in combination with CpG-oligodeoxynucleotides in the induction of higher numbers of antigen-specific T cells compared to vaccination with free TRP2. Here, we present further data with regard to optimal antigen dose, the relevance of vaccine injection site and on the T cell stimulatory synergism of liposomal adjuvant combinations. Compared to an aqueous solution liposomal TRP2 was more potent in the induction of TRP2-specific T cells at an optimal dose but showed a narrow dose optimum with profoundly impaired T cell responses at higher vaccine doses. Higher T cell numbers were induced when mice were vaccinated into their hint foodpads compared to intradermal vaccination, the site used routinely in murine tumor vaccination models. A synergistic adjuvant effect was observed when CpG-oligodeoxynucleotides were admixed with liposomal monophosphoryl lipid A (MPLA) and the lipopeptide Pam3Cys, respectively. In summary our data demonstrate that liposomes as carriers for peptide-antigen and adjuvant induce a strong antigen-specific T cell response and are superior over vaccine formulations composed of free peptide and adjuvant.
{"title":"Liposome-Encapsulated Adjuvants are Potent Inducers of Antigen- Specific T-Cells in Vivo","authors":"A. Konur, A. Graser, I. Klamp, S. Kreiter, Abderraouf Selmi, M. Diken, C. Huber, Ö. Türeci, U. Şahin","doi":"10.2174/1874079000802010015","DOIUrl":"https://doi.org/10.2174/1874079000802010015","url":null,"abstract":"As shown previously, encapsulation of a peptide derived from tyrosinase-related protein2 (TRP2) into liposomes (artificial virus envelope (AVE) 3) resulted in combination with CpG-oligodeoxynucleotides in the induction of higher numbers of antigen-specific T cells compared to vaccination with free TRP2. Here, we present further data with regard to optimal antigen dose, the relevance of vaccine injection site and on the T cell stimulatory synergism of liposomal adjuvant combinations. Compared to an aqueous solution liposomal TRP2 was more potent in the induction of TRP2-specific T cells at an optimal dose but showed a narrow dose optimum with profoundly impaired T cell responses at higher vaccine doses. Higher T cell numbers were induced when mice were vaccinated into their hint foodpads compared to intradermal vaccination, the site used routinely in murine tumor vaccination models. A synergistic adjuvant effect was observed when CpG-oligodeoxynucleotides were admixed with liposomal monophosphoryl lipid A (MPLA) and the lipopeptide Pam3Cys, respectively. In summary our data demonstrate that liposomes as carriers for peptide-antigen and adjuvant induce a strong antigen-specific T cell response and are superior over vaccine formulations composed of free peptide and adjuvant.","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"2 1","pages":"15-24"},"PeriodicalIF":0.0,"publicationDate":"2008-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68051069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-06-12DOI: 10.2174/1874079000802010012
V. Pak
An anticancer "magic bullet" should have both efficacy and specificity parts. We have used an effective Apop- tosis I nducer t o t rigger t he apoptosis. A lpha-fetoprotein w as us ed t o de liver A poptosis I nducers s pecifically t o cancer cells. The AFP-AI complex inhibited tumor growth in mice, enlarged mice life survival and has shown a 50% response in patients with metastatic colorectal cancer.
{"title":"The Use of AFP-Complexes to Induce Apoptosis in Cancer Cells~!2008-03-12~!2008-05-20~!2008-06-12~!","authors":"V. Pak","doi":"10.2174/1874079000802010012","DOIUrl":"https://doi.org/10.2174/1874079000802010012","url":null,"abstract":"An anticancer \"magic bullet\" should have both efficacy and specificity parts. We have used an effective Apop- tosis I nducer t o t rigger t he apoptosis. A lpha-fetoprotein w as us ed t o de liver A poptosis I nducers s pecifically t o cancer cells. The AFP-AI complex inhibited tumor growth in mice, enlarged mice life survival and has shown a 50% response in patients with metastatic colorectal cancer.","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"2 1","pages":"12-14"},"PeriodicalIF":0.0,"publicationDate":"2008-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68051028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-06-12DOI: 10.2174/1874079000802010005
M. B. Y. Jonage-Canonico, V. Lenoir, B. Vivien‐Roels, P. Pévet, R. Scholler, B. Kerdelhué
A single intragastric administration of 7,12-dimethylbenz(a)anthracene (DMBA) has been shown to induce mammary tumors in young cycling female Sprague-Dawley rats. The appearance of the tumors is preceded, during the la- tency phase, by a series of neuroendocrine disturbances, including attenuation of the preovulatory Luteinizing Hormone surge and Gonadotropin-Releasing Hormone release and amplification of the preovulatory 17� -Estradiol (E2) surge. Also, E2 treatment leads to a complete blunting of the Isoproterenol-induced stimulation of Melatonin secretion.In this study, we examined the hypothesis that Tamoxifen, an antagonist of E2, would stimulate the Isoproterenol-induced Mela- tonin (MT) secretion from the pineal gland, during the latency phase. Sprague-Dawley rats, 55-60 days of age, received, on the Estrous day of the Estrous cycle, a single dose of 15 mg DMBA delivered by intragastric intubation. In order to avoid possible interactions with endogenous steroids or mammary tumor- derived compounds, they were ovariectomized 5 days later and, one month later, sacrificed by decapitation at 10 a.m. Then, pineal glands were removed and placed in perifusion chambers containing Hanks 199 medium. The medium was satured with O2/CO2 (95 %/5 %) and its pH was 7.4. Ten independent chambers were immersed in a water bath at 37°C. Each pineal gland received medium (flow rate : 0.16 ml/min) through a system of input lines. The fractions were collected every 10 min, and immediately frozen at -20°C until Melatonin RIA. Experiments were repeated to obtain up to five ex- perimental points for each treatment. Tamoxifen (10 -9 to 10 -7 M) was applied during the entire perifusion period (7 hours). Isoproterenol (10 -6 M) was applied for 20 min after 3 hours in perifusion. Melatonin concentrations and Areas Under the Curves were compared using two-factor ANOVA as well as parametric or nonparametric two-sample methods after test- ing sample normality. In vehicle treated rats, Tamoxifen treatment, at the concentration of 10 -9 M, leads to a non significant amplification of the Isoproterenol-induced stimulation of Melatonin secretion. In DMBA-treated rats, Tamoxifen treatment leads,starting from 10 -9 M to a dose- dependent increase (up to 400% in- crease) of the Isoproterenol-induced stimulation of Melatonin . The results suggest that in addition to the well documented beneficial effects of Tamoxifen at the mammary gland level, this E2 antagonist may also have, after DMBA treatment, an additional beneficial effect at the pineal gland level through- out the stimulation of Melatonin, which exerts an inhibitory action on the induction and on the growth of breast cancers.
{"title":"Tamoxifen Stimulates Melatonin Secretion After Exposure to a Mammary Carcinogen, the Dimethyl Benz(a)Anthracene, in Sprague Dawley Female Rat","authors":"M. B. Y. Jonage-Canonico, V. Lenoir, B. Vivien‐Roels, P. Pévet, R. Scholler, B. Kerdelhué","doi":"10.2174/1874079000802010005","DOIUrl":"https://doi.org/10.2174/1874079000802010005","url":null,"abstract":"A single intragastric administration of 7,12-dimethylbenz(a)anthracene (DMBA) has been shown to induce mammary tumors in young cycling female Sprague-Dawley rats. The appearance of the tumors is preceded, during the la- tency phase, by a series of neuroendocrine disturbances, including attenuation of the preovulatory Luteinizing Hormone surge and Gonadotropin-Releasing Hormone release and amplification of the preovulatory 17� -Estradiol (E2) surge. Also, E2 treatment leads to a complete blunting of the Isoproterenol-induced stimulation of Melatonin secretion.In this study, we examined the hypothesis that Tamoxifen, an antagonist of E2, would stimulate the Isoproterenol-induced Mela- tonin (MT) secretion from the pineal gland, during the latency phase. Sprague-Dawley rats, 55-60 days of age, received, on the Estrous day of the Estrous cycle, a single dose of 15 mg DMBA delivered by intragastric intubation. In order to avoid possible interactions with endogenous steroids or mammary tumor- derived compounds, they were ovariectomized 5 days later and, one month later, sacrificed by decapitation at 10 a.m. Then, pineal glands were removed and placed in perifusion chambers containing Hanks 199 medium. The medium was satured with O2/CO2 (95 %/5 %) and its pH was 7.4. Ten independent chambers were immersed in a water bath at 37°C. Each pineal gland received medium (flow rate : 0.16 ml/min) through a system of input lines. The fractions were collected every 10 min, and immediately frozen at -20°C until Melatonin RIA. Experiments were repeated to obtain up to five ex- perimental points for each treatment. Tamoxifen (10 -9 to 10 -7 M) was applied during the entire perifusion period (7 hours). Isoproterenol (10 -6 M) was applied for 20 min after 3 hours in perifusion. Melatonin concentrations and Areas Under the Curves were compared using two-factor ANOVA as well as parametric or nonparametric two-sample methods after test- ing sample normality. In vehicle treated rats, Tamoxifen treatment, at the concentration of 10 -9 M, leads to a non significant amplification of the Isoproterenol-induced stimulation of Melatonin secretion. In DMBA-treated rats, Tamoxifen treatment leads,starting from 10 -9 M to a dose- dependent increase (up to 400% in- crease) of the Isoproterenol-induced stimulation of Melatonin . The results suggest that in addition to the well documented beneficial effects of Tamoxifen at the mammary gland level, this E2 antagonist may also have, after DMBA treatment, an additional beneficial effect at the pineal gland level through- out the stimulation of Melatonin, which exerts an inhibitory action on the induction and on the growth of breast cancers.","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"2 1","pages":"5-11"},"PeriodicalIF":0.0,"publicationDate":"2008-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68051016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-01-01DOI: 10.2174/1874079000802010001
Manolis C Demetriou, Kevin A Kwei, Marianne B Powell, Raymond B Nagle, G Tim Bowden, Anne E Cress
We have previously identified a structural variant of the α6 integrin (Laminin receptor) called α6p. The α6p variant is a 70 kDa form of the full-length α6 integrin (140 kDa) that remains paired with either the β1 or β4 subunit on the cell surface. α6p is produced by urokinase-type plasminogen activator (uPA), which removes the extracellular β-barrel domain while the receptor is on the cell surface. The α6p integrin was present in human prostate cancer tissue but not in normal tissue and the cleavage of the α6 integrin extracellular domain promotes tumor cell invasion and migration on laminin. The objective of the present study was to determine whether the α6p integrin is observed in other models of carcinogenesis. Our results indicate detectable low levels of α6p in normal mouse skin, and comparatively elevated levels in mouse papillomas and squamous cell carcinomas induced by DMBA, TPA and MNNG treatments. Furthermore, we have found that α6p was present at high levels in skin melanomas of transgenic mice that over express activated Ha-ras under the control of the tyrosinase promoter. Finally, subcutaneous injection into athymic nude mice of a malignant mouse keratinocyte derived cell line (6M90) that is α6p negative, results in the development of tumors that contain α6p integrin. The latter results indicate that α6p is induced in vivo suggesting that the tumor microenvironment plays a major role in the production of α6p. Taken together, these data suggest that the cell surface cleavage of the α6 integrin may be a novel mechanism of integrin regulation and might be an important step during skin tissue remodeling and during carcinogenesis.
{"title":"Integrin A6 Cleavage in Mouse Skin Tumors.","authors":"Manolis C Demetriou, Kevin A Kwei, Marianne B Powell, Raymond B Nagle, G Tim Bowden, Anne E Cress","doi":"10.2174/1874079000802010001","DOIUrl":"https://doi.org/10.2174/1874079000802010001","url":null,"abstract":"<p><p>We have previously identified a structural variant of the α6 integrin (Laminin receptor) called α6p. The α6p variant is a 70 kDa form of the full-length α6 integrin (140 kDa) that remains paired with either the β1 or β4 subunit on the cell surface. α6p is produced by urokinase-type plasminogen activator (uPA), which removes the extracellular β-barrel domain while the receptor is on the cell surface. The α6p integrin was present in human prostate cancer tissue but not in normal tissue and the cleavage of the α6 integrin extracellular domain promotes tumor cell invasion and migration on laminin. The objective of the present study was to determine whether the α6p integrin is observed in other models of carcinogenesis. Our results indicate detectable low levels of α6p in normal mouse skin, and comparatively elevated levels in mouse papillomas and squamous cell carcinomas induced by DMBA, TPA and MNNG treatments. Furthermore, we have found that α6p was present at high levels in skin melanomas of transgenic mice that over express activated Ha-ras under the control of the tyrosinase promoter. Finally, subcutaneous injection into athymic nude mice of a malignant mouse keratinocyte derived cell line (6M90) that is α6p negative, results in the development of tumors that contain α6p integrin. The latter results indicate that α6p is induced in vivo suggesting that the tumor microenvironment plays a major role in the production of α6p. Taken together, these data suggest that the cell surface cleavage of the α6 integrin may be a novel mechanism of integrin regulation and might be an important step during skin tissue remodeling and during carcinogenesis.</p>","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"2 ","pages":"1-4"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906811/pdf/nihms121916.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29151589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2007-12-06DOI: 10.2174/1874079000701010009
I. Macpherson, Robert J. Jones, T. Evans
Currently available systemic therapies for malignant melanoma are unsatisfactory and there is an urgent need for effective and well tolerated drugs for use in both early and advanced disease. The Src family of cytoplasmic tyrosine kinases (SFKs) have been implicated in the regulation of many of the hallmarks of malignancy making them attractive targets in solid tumours including melanoma. The first generation of selective SFK inhibitors to enter the clinic (AZD0530, dasatinib, bosutinib) have demonstrated safety, tolerability and target modulation in phase I trials. Phase II trials in patients with advanced melanoma are now planned in the USA and Europe. Here we discuss the rationale for, and challenges facing, the successful development of SFK inhibitors in melanoma. Furthermore, as dasatinib is also a potent inhibitor of the receptor tyrosine kinase (RTK), c-Kit, we reconsider the utility of targeting this kinase in the light of re- cent molecular epidemiological data.
{"title":"Clinical Development of Src Family Kinase Inhibitors in Malignant Melanoma","authors":"I. Macpherson, Robert J. Jones, T. Evans","doi":"10.2174/1874079000701010009","DOIUrl":"https://doi.org/10.2174/1874079000701010009","url":null,"abstract":"Currently available systemic therapies for malignant melanoma are unsatisfactory and there is an urgent need for effective and well tolerated drugs for use in both early and advanced disease. The Src family of cytoplasmic tyrosine kinases (SFKs) have been implicated in the regulation of many of the hallmarks of malignancy making them attractive targets in solid tumours including melanoma. The first generation of selective SFK inhibitors to enter the clinic (AZD0530, dasatinib, bosutinib) have demonstrated safety, tolerability and target modulation in phase I trials. Phase II trials in patients with advanced melanoma are now planned in the USA and Europe. Here we discuss the rationale for, and challenges facing, the successful development of SFK inhibitors in melanoma. Furthermore, as dasatinib is also a potent inhibitor of the receptor tyrosine kinase (RTK), c-Kit, we reconsider the utility of targeting this kinase in the light of re- cent molecular epidemiological data.","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"1 1","pages":"9-20"},"PeriodicalIF":0.0,"publicationDate":"2007-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68050968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2007-01-01DOI: 10.2174/1874079000701010001
A. Romano, Marleen Baars, H. Martens, R. Brandão, Y. Detisch, Eveline, Jongen, M. Blok, P. Lindsey, D. Fischer, E. García
Background: More than half of the families with breast and/or ovarian cancer (BC/OC) have no BRCA1 or BRCA2 mutation, moreover the broad lifetime risks reported within families with a BRCA1/2 mutation suggest other genes are also responsible. Objective: Assess the prevalence, gene-gene and phenotype-genotype associations of two functional progesterone receptor polymorphisms (PRP), PROGINS and +331G/A, in familial BC/OC. Methods: DNA samples from 318 randomly selected probands tested for BRCA1/2 mutations were genotyped for the PRP and CHEK2*1100delC variant. Results: BRCA1 was associated with BC at young age, p=0.002; +331A marginally with OC, p=0.07, and PROGINS with male BC, p=0.04. Homozygous +331A/A co-segregated with BRCA2 variants more frequently than expected by chance alone. Co-occurrence of +331A with a BRCA1BRCA2 mutation was associated with multiple BC events compared to +331A or BRCA1/BRCA2 alone, p=0.02. Conclusions: The PRP are risk factors for familial BC/OC, and +331A allele is a gene modifier of BRCA1 and BRCA2.
{"title":"Impact of Two Functional Progesterone Receptor Polymorphisms (PRP): +331G/A and PROGINS on the Cancer Risks in Familial Breast/Ovarian Cancer","authors":"A. Romano, Marleen Baars, H. Martens, R. Brandão, Y. Detisch, Eveline, Jongen, M. Blok, P. Lindsey, D. Fischer, E. García","doi":"10.2174/1874079000701010001","DOIUrl":"https://doi.org/10.2174/1874079000701010001","url":null,"abstract":"Background: More than half of the families with breast and/or ovarian cancer (BC/OC) have no BRCA1 or BRCA2 mutation, moreover the broad lifetime risks reported within families with a BRCA1/2 mutation suggest other genes are also responsible. Objective: Assess the prevalence, gene-gene and phenotype-genotype associations of two functional progesterone receptor polymorphisms (PRP), PROGINS and +331G/A, in familial BC/OC. Methods: DNA samples from 318 randomly selected probands tested for BRCA1/2 mutations were genotyped for the PRP and CHEK2*1100delC variant. Results: BRCA1 was associated with BC at young age, p=0.002; +331A marginally with OC, p=0.07, and PROGINS with male BC, p=0.04. Homozygous +331A/A co-segregated with BRCA2 variants more frequently than expected by chance alone. Co-occurrence of +331A with a BRCA1BRCA2 mutation was associated with multiple BC events compared to +331A or BRCA1/BRCA2 alone, p=0.02. Conclusions: The PRP are risk factors for familial BC/OC, and +331A allele is a gene modifier of BRCA1 and BRCA2.","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"1 1","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68050959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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