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Muscling in on atherosclerosis
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testing also fear that patient records might not be kept anonymous, and that companies could refuse them health insurance if they were found to carry genes that predispose them to cancer. ‘We are very sensitive to the ethical and social issues that this programme raises,’ stressed Anton-Culver. ‘Ethicists and representatives of cancer patients were involved
MOLECULAR MEDICINE TODAY, NOVEMBER 1998
in the decision-making process behind setting up the new network. The consent forms have been designed with great care and we hope that people’s fear about the network will be allayed when the benefits become apparent. In 2–3 years’ time I expect to be participating in a resource that will provide support on several levels. Scientists will gain increased knowledge
about cancer susceptibility, patients will receive improved genetic counselling as a result of better feedback, and practising physicians will have access to an infrastructure that will allow fast and efficient transmission of relevant information.’ Kathryn Senior
Space-filling model of epothilone. Kindly provided by Michael Siani, Kosan Biosciences, Burlingame, CA, USA.
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Towards the biosynthesis of an alternative to Taxol Kosan Biosciences (Burlingame, CA, USA) has received a Phase I Small Business Innovative Research Grant from the US National Cancer Institute to support their work on the biosynthetic pathway of the epothilones, a group of polyketides first isolated from the soil myxobacterium Sorangium cellulosum, as potential alternatives to the anticancer drug paclitaxel (Taxol). ‘We would anticipate that epothilones, if proven to be safe and effective, would find use as a treatment for Taxol-resistant tumors and other tumor types found to be responsive to Taxol. Taxol is particularly effective in ovarian and breast cancers, and its range of applications is expanding,’ says Michael Ostrach, Chief Operating Officer of Kosan. During cell division, a dynamic process of tubulin polymerization and depolymerization transforms cytoskeletal microtubules into the
mitotic spindle. The epothilones, like paclitaxel, stabilize microtubules by binding to tubulin, thus preventing spindle formation and blocking mitosis. ‘Two decades after the discovery of Taxol, epothilones represent the first class of compounds that mimic the microtubulestabilizing effect of the taxane structure,’ says Ostrach.’ Unlike paclitaxel, the epothilones do not appear to possess endotoxin-like properties, which may be responsible for some of the drug’s side effects. Between five and 50 bacterial enzymes and carrier proteins are involved in the biosynthesis of polyketide molecules, and are collectively known as polyketide synthases (PKS). Each PKS is encoded by a gene cluster, so once a component of the gene cluster has been identified, the whole cluster can be sequenced, thus providing the code for the entire biosynthetic pathway.
Scientists at Kosan will develop an over-expression system, probably in Streptomyces spp., Escherichia coli, or yeast, to produce the epothilones in large quantities for therapeutic use. Small amounts of epothilone – sufficient for in vitro and animal studies – have been produced by fermenting myxobacteria, but the organisms grow too slowly and do not produce sufficient quantities of epothilone for industrial production. ‘We would hope that more developed production organisms would be more economical,’ says Ostrach. Future plans include the production of epothilone analogues by modifying the gene cluster. Sharon Dorrell
Muscling in on atherosclerosis A new collaboration between the Hoechst– ARIAD Genomics Center (Cambridge, MA, USA) and the Center for the Prevention of Cardiovascular Disease (CPCD, Harvard School for Public Health, Boston, MA, USA) will use functional genomics to find targets for the development of new therapies for cardiovascular disease. Dr Arthur Lee (Director, CPCD), and his colleagues have developed a model for atherosclerosis based on the murine cell line Monc-1, in which proliferating cells are induced to differentiate into smooth muscle cells. A number of genes are switched on during this process and researchers at the CPCD have found that genes in aortic smooth muscle cells behave in a similar way. Our idea is that atherosclerosis can occur when the normal cells have been de-differentiated so they begin to proliferate. We
460
are trying to find the genes that cause this proliferation,’ explains Dr Mark Zoller (Director, Hoechst–ARIAD Genomics Center). The research teams led by Dr Zoller and Dr Lee plan to identify the genes differentially expressed in the differentiated and undifferentiated cells by hybridizing the mRNA produced by the cells to DNA chips. ‘The genes on the chips represent every known gene to date, from full-length cDNA sequences, genomic sequences, expressed sequence tags or partial cDNA sequences. The goal is to have a chip with one fragment from each gene,’ explains Zoller. At present, the chips contain approximately 30–40% of known human and mouse genes and, if necessary, they can be biased towards genes expressed in specific tissues. Once the differentially expressed genes have been identified, cell culture systems and animal
models will be used to investigate the effects of stimulating or inhibiting the expression of these genes. It will then be up to the drug development teams at Hoechst Marion Roussel and ARIAD Pharmaceuticals to design therapies to target these genes or the proteins they encode, thereby preventing vascular smooth muscle cell (VSMC) proliferation and atherosclerosis. Researchers at Hoechst Marion Roussel in Frankfurt are also attempting to characterize the signals produced by vascular endothelial cells that trigger proliferation of smooth muscle cells. VSMC proliferation is also closely involved in tumor angiogenesis, so it is quite possible that a useful byproduct of this effort will be compounds that block tumor neovascularization. Sharon Dorrell
ISSN/98/$ - see front matter © 1998 Elsevier Science All rights reserved.
w
s
testing also fear that patient records might not be kept anonymous, and that companies could refuse them health insurance if they were found to carry genes that predispose them to cancer. ‘We are very sensitive to the ethical and social issues that this programme raises,’ stressed Anton-Culver. ‘Ethicists and representatives of cancer patients were involved
MOLECULAR MEDICINE TODAY, NOVEMBER 1998
in the decision-making process behind setting up the new network. The consent forms have been designed with great care and we hope that people’s fear about the network will be allayed when the benefits become apparent. In 2–3 years’ time I expect to be participating in a resource that will provide support on several levels. Scientists will gain increased knowledge
about cancer susceptibility, patients will receive improved genetic counselling as a result of better feedback, and practising physicians will have access to an infrastructure that will allow fast and efficient transmission of relevant information.’ Kathryn Senior
Space-filling model of epothilone. Kindly provided by Michael Siani, Kosan Biosciences, Burlingame, CA, USA.
N
Towards the biosynthesis of an alternative to Taxol Kosan Biosciences (Burlingame, CA, USA) has received a Phase I Small Business Innovative Research Grant from the US National Cancer Institute to support their work on the biosynthetic pathway of the epothilones, a group of polyketides first isolated from the soil myxobacterium Sorangium cellulosum, as potential alternatives to the anticancer drug paclitaxel (Taxol). ‘We would anticipate that epothilones, if proven to be safe and effective, would find use as a treatment for Taxol-resistant tumors and other tumor types found to be responsive to Taxol. Taxol is particularly effective in ovarian and breast cancers, and its range of applications is expanding,’ says Michael Ostrach, Chief Operating Officer of Kosan. During cell division, a dynamic process of tubulin polymerization and depolymerization transforms cytoskeletal microtubules into the
mitotic spindle. The epothilones, like paclitaxel, stabilize microtubules by binding to tubulin, thus preventing spindle formation and blocking mitosis. ‘Two decades after the discovery of Taxol, epothilones represent the first class of compounds that mimic the microtubulestabilizing effect of the taxane structure,’ says Ostrach.’ Unlike paclitaxel, the epothilones do not appear to possess endotoxin-like properties, which may be responsible for some of the drug’s side effects. Between five and 50 bacterial enzymes and carrier proteins are involved in the biosynthesis of polyketide molecules, and are collectively known as polyketide synthases (PKS). Each PKS is encoded by a gene cluster, so once a component of the gene cluster has been identified, the whole cluster can be sequenced, thus providing the code for the entire biosynthetic pathway.
Scientists at Kosan will develop an over-expression system, probably in Streptomyces spp., Escherichia coli, or yeast, to produce the epothilones in large quantities for therapeutic use. Small amounts of epothilone – sufficient for in vitro and animal studies – have been produced by fermenting myxobacteria, but the organisms grow too slowly and do not produce sufficient quantities of epothilone for industrial production. ‘We would hope that more developed production organisms would be more economical,’ says Ostrach. Future plans include the production of epothilone analogues by modifying the gene cluster. Sharon Dorrell
Muscling in on atherosclerosis A new collaboration between the Hoechst– ARIAD Genomics Center (Cambridge, MA, USA) and the Center for the Prevention of Cardiovascular Disease (CPCD, Harvard School for Public Health, Boston, MA, USA) will use functional genomics to find targets for the development of new therapies for cardiovascular disease. Dr Arthur Lee (Director, CPCD), and his colleagues have developed a model for atherosclerosis based on the murine cell line Monc-1, in which proliferating cells are induced to differentiate into smooth muscle cells. A number of genes are switched on during this process and researchers at the CPCD have found that genes in aortic smooth muscle cells behave in a similar way. Our idea is that atherosclerosis can occur when the normal cells have been de-differentiated so they begin to proliferate. We
460
are trying to find the genes that cause this proliferation,’ explains Dr Mark Zoller (Director, Hoechst–ARIAD Genomics Center). The research teams led by Dr Zoller and Dr Lee plan to identify the genes differentially expressed in the differentiated and undifferentiated cells by hybridizing the mRNA produced by the cells to DNA chips. ‘The genes on the chips represent every known gene to date, from full-length cDNA sequences, genomic sequences, expressed sequence tags or partial cDNA sequences. The goal is to have a chip with one fragment from each gene,’ explains Zoller. At present, the chips contain approximately 30–40% of known human and mouse genes and, if necessary, they can be biased towards genes expressed in specific tissues. Once the differentially expressed genes have been identified, cell culture systems and animal
models will be used to investigate the effects of stimulating or inhibiting the expression of these genes. It will then be up to the drug development teams at Hoechst Marion Roussel and ARIAD Pharmaceuticals to design therapies to target these genes or the proteins they encode, thereby preventing vascular smooth muscle cell (VSMC) proliferation and atherosclerosis. Researchers at Hoechst Marion Roussel in Frankfurt are also attempting to characterize the signals produced by vascular endothelial cells that trigger proliferation of smooth muscle cells. VSMC proliferation is also closely involved in tumor angiogenesis, so it is quite possible that a useful byproduct of this effort will be compounds that block tumor neovascularization. Sharon Dorrell
ISSN/98/$ - see front matter © 1998 Elsevier Science All rights reserved.