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New screening test for colorectal cancer gets off to a good start
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New screening test for colorectal cancer gets off to a good start US researchers are excited by the results of a small pilot study of a DNA test for colorectal cancer. David Ahlquist (Mayo Clinic, Rochester, MN, USA) and colleagues at the Mayo Clinic and EXACT Laboratories (Maynard, MA, USA) are investigating a multitarget assay to look for altered human DNA in stool samples. In their study, published in Gastroenterology (2000; 119: 1219–27), tumours were detected with 91% sensitivity and 100% specificity. “The results exceeded our expectations”, says Ahlquist; “20 out of 22 tumours analysed were positive with the DNA test, as were 73% of large adenomas.” Colorectal cancers accumulate many DNA mutations during their development, often in the K-RAS, P53, and APC genes. Tumours from different patients may have many genetic changes in common. However, no one change is found in all colorectal cancers. Consequently, tests designed to pick up single mutations in DNA released into stools by exfoliating tumour cells miss many tumours. Ahlquist and colleagues have got round this problem by testing stool
DNA for a panel of genetic markers. This includes 15 point mutations in KRAS, P53, and APC, and a microsatellite instability marker. They also measured what they call long DNA in stool samples. “When normal cells slough off from the mucosa they apoptose”, explains Ahlquist, “and their DNA is chopped into small pieces. By contrast, exfoliated tumour cells do not apoptose and much longer DNA is released into the stool. Measurement of long DNA was a very informative part of the panel, and we have preliminary results that indicate that this particular marker may detect supracolonic cancer as well as colorectal cancer.” Eventually, suggests Ahlquist, it may also be possible to
predict the behaviour and site of the lesion by looking at the profile of DNA abnormalities detected in this way. “This new form of screening may have great potential for the future”, comments Wendy Atkin of the Imperial Cancer Research Fund Colorectal Cancer Unit at St Mark’s Hospital, London, UK, “but it is early days, and these findings need to be replicated in larger studies.” Ahlquist, meanwhile, is planning a US$4.9 million (£2.78 million) multicentre study, involving 3000 patients from the general population. The study, funded by the US National Cancer Institute, will start in January, 2001. Jane Bradbury
Colon cancer screening in the USA and the UK Several screening approaches are advocated by the American Cancer Society, explains Ahlquist. “For the average-risk population, the Society recommends faecal occult blood testing annually, sigmoidoscopy every 5 years from age 50, or a barium X ray every 5 – 10 years from age 50. There is also increasing advocacy for colonoscopy every 10 years. “In the UK, two 2-year pilot studies of screening by faecal occult blood testing, each involving one million patients, are underway”, explains Atkin. “I am also involved in a large study of screening by flexible sigmoidoscopy. I think the UK Department of Health will wait for the results of all these studies before deciding on a national screening programme.”
Australian scientists design novel antiangiogenic weapon
Courtesy of P Hogg
When Philip Hogg and Neil Donoghue at the University of New South Wales (Sydney, Australia) designed the molecule glutathione arsenoxide (GSAO), they did not know they had invented a potential anticancer drug. They simply wanted to use the molecule to identify cell-surface proteins whose activity is controlled by rearrangement of disulphide bonds in a redox reaction. Hogg and colleagues
Effect of GSAO (bottom row) or vehicle (top row) on xenotransplanted human pancreatic tumours THE LANCET Oncology Vol 1 December 2000
identifed about ten proteins on the surface of endothelial cells, among them protein disulphide isomerase, that incorporated GSAO (Protein Science, in press). “GSAO is a selective inhibitor of proliferating endothelial cells in culture and angiogenesis in the chick chorioallantoic membrane (CAM) assay”, explains Hogg. “These effects on endothelial cells translate into a remarkable inhibition – at least 70% – of the growth rate of both murine and human tumours in mice. There was a marked reduction in the vasculature of the treated tumours, no change in the proliferative rate and an increase in the tumour-cell apoptotic index – this is what you would expect with an antiangiogenic agent.” GSAO is extremely water soluble and is orally available, which is a key advantage because an antiangiogenic agent is likely to be used long term, in combination with chemotherapy or
radiotherapy. Because it is water soluble, it is also excreted rapidly and does not accumulate anywhere in the body except the tumour. The rapid excretion and limited entry into cells may account for its lack of toxicity in mice. Clinical phase I trials are due to start towards the end of next year. To produce and develop GSAO locally, the University of New South Wales teamed up with the Australian companies Unisearch and IDT to facilitate bringing the drug onto the market more cheaply and more quickly than would be possible without collaboration. Meanwhile, Hogg is investigating the mechanism of GSAO’s antiangiogenic action. “Presumably, it is working by inactivating an important redox reaction on the surface of endothelial cells”, he says, “but as yet we don’t know what that reaction is.” Martina Habeck
199
For personal use only. Not to be reproduced without permission of The Lancet.
New screening test for colorectal cancer gets off to a good start US researchers are excited by the results of a small pilot study of a DNA test for colorectal cancer. David Ahlquist (Mayo Clinic, Rochester, MN, USA) and colleagues at the Mayo Clinic and EXACT Laboratories (Maynard, MA, USA) are investigating a multitarget assay to look for altered human DNA in stool samples. In their study, published in Gastroenterology (2000; 119: 1219–27), tumours were detected with 91% sensitivity and 100% specificity. “The results exceeded our expectations”, says Ahlquist; “20 out of 22 tumours analysed were positive with the DNA test, as were 73% of large adenomas.” Colorectal cancers accumulate many DNA mutations during their development, often in the K-RAS, P53, and APC genes. Tumours from different patients may have many genetic changes in common. However, no one change is found in all colorectal cancers. Consequently, tests designed to pick up single mutations in DNA released into stools by exfoliating tumour cells miss many tumours. Ahlquist and colleagues have got round this problem by testing stool
DNA for a panel of genetic markers. This includes 15 point mutations in KRAS, P53, and APC, and a microsatellite instability marker. They also measured what they call long DNA in stool samples. “When normal cells slough off from the mucosa they apoptose”, explains Ahlquist, “and their DNA is chopped into small pieces. By contrast, exfoliated tumour cells do not apoptose and much longer DNA is released into the stool. Measurement of long DNA was a very informative part of the panel, and we have preliminary results that indicate that this particular marker may detect supracolonic cancer as well as colorectal cancer.” Eventually, suggests Ahlquist, it may also be possible to
predict the behaviour and site of the lesion by looking at the profile of DNA abnormalities detected in this way. “This new form of screening may have great potential for the future”, comments Wendy Atkin of the Imperial Cancer Research Fund Colorectal Cancer Unit at St Mark’s Hospital, London, UK, “but it is early days, and these findings need to be replicated in larger studies.” Ahlquist, meanwhile, is planning a US$4.9 million (£2.78 million) multicentre study, involving 3000 patients from the general population. The study, funded by the US National Cancer Institute, will start in January, 2001. Jane Bradbury
Colon cancer screening in the USA and the UK Several screening approaches are advocated by the American Cancer Society, explains Ahlquist. “For the average-risk population, the Society recommends faecal occult blood testing annually, sigmoidoscopy every 5 years from age 50, or a barium X ray every 5 – 10 years from age 50. There is also increasing advocacy for colonoscopy every 10 years. “In the UK, two 2-year pilot studies of screening by faecal occult blood testing, each involving one million patients, are underway”, explains Atkin. “I am also involved in a large study of screening by flexible sigmoidoscopy. I think the UK Department of Health will wait for the results of all these studies before deciding on a national screening programme.”
Australian scientists design novel antiangiogenic weapon
Courtesy of P Hogg
When Philip Hogg and Neil Donoghue at the University of New South Wales (Sydney, Australia) designed the molecule glutathione arsenoxide (GSAO), they did not know they had invented a potential anticancer drug. They simply wanted to use the molecule to identify cell-surface proteins whose activity is controlled by rearrangement of disulphide bonds in a redox reaction. Hogg and colleagues
Effect of GSAO (bottom row) or vehicle (top row) on xenotransplanted human pancreatic tumours THE LANCET Oncology Vol 1 December 2000
identifed about ten proteins on the surface of endothelial cells, among them protein disulphide isomerase, that incorporated GSAO (Protein Science, in press). “GSAO is a selective inhibitor of proliferating endothelial cells in culture and angiogenesis in the chick chorioallantoic membrane (CAM) assay”, explains Hogg. “These effects on endothelial cells translate into a remarkable inhibition – at least 70% – of the growth rate of both murine and human tumours in mice. There was a marked reduction in the vasculature of the treated tumours, no change in the proliferative rate and an increase in the tumour-cell apoptotic index – this is what you would expect with an antiangiogenic agent.” GSAO is extremely water soluble and is orally available, which is a key advantage because an antiangiogenic agent is likely to be used long term, in combination with chemotherapy or
radiotherapy. Because it is water soluble, it is also excreted rapidly and does not accumulate anywhere in the body except the tumour. The rapid excretion and limited entry into cells may account for its lack of toxicity in mice. Clinical phase I trials are due to start towards the end of next year. To produce and develop GSAO locally, the University of New South Wales teamed up with the Australian companies Unisearch and IDT to facilitate bringing the drug onto the market more cheaply and more quickly than would be possible without collaboration. Meanwhile, Hogg is investigating the mechanism of GSAO’s antiangiogenic action. “Presumably, it is working by inactivating an important redox reaction on the surface of endothelial cells”, he says, “but as yet we don’t know what that reaction is.” Martina Habeck
199
For personal use only. Not to be reproduced without permission of The Lancet.