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Could dogs track down prostate cancer?
Newsdesk Enzyme’s dual role has implications for cancer treatment take part in signalling. “The peroxiredoxins act as a peroxide floodgate, keeping these molecules away from susceptible targets until the floodgate is opened”, explains Wood. But, “when a cell produces H2O2 in a concentrated burst, it overwhelms and inactivates the
Courtesy of Z Wood
A new finding that links overexpression of peroxiredoxins—a group of enzymes that catalyse the reduction of oxidative substances—to apoptosis resistance in cancer cells suggests that inhibiting these enzymes may improve therapy. In bacteria, peroxiredoxins help the organism avoid degredation by their host through detoxification of hydrogen peroxide (H2O2). But, eukaryotic versions of the peroxiredoxins become inactivated by high concentrations of H2O2, enabling it to accumulate inside the cell. “Mammalian cells could easily have mutated to rid themselves of this sensitivity [to H2O2], but they didn’t”, says Zachary Wood, Oregon State University (USA). “So, we deduced that it must provide some advantage.” Wood and colleagues from Wake Forest University (NC, USA) came up with a theory called the floodgate hypothesis (Science 2003; 300: 650–53) to explain their findings. They believe peroxiredoxin inactivation constitutes a cellular switch, which enables mammalian cells to use H2O2 as a signalling molecule. In resting cells, large amounts of peroxiredoxins keep the concentration of H2O2 low, so it cannot
Differences between the prokaryotic (purple) and eukaryotic (yellow) forms of peroxiredoxin.
peroxiredoxin enzymes”, so H2O2 is free to accumulate in the cell. “Here, the floodgate appears too strong and remains unopened despite an H2O2 pulse”, he says. H2O2 can react with thiols on proteins involved in the NFB and
MAP kinase signalling pathways starting a chain of events that leads to apoptosis. “Some cancer cell lines overexpress peroxiredoxins and are therefore protected from killing by tumour necrosis factors and cisplatin”, which use H2O2 to activate apoptotic pathways, he adds. However, Wood and co-workers were puzzled by the observation that peroxiredoxin inactivation seemed to be irreversible. If this observation was correct, it would limit the effectiveness of any signalling system. But, a related paper published in the same issue of Science (2003; 300: 653–56) proves that the inactivation is reversible in vivo. Sue Goo Rhee and colleagues from the National Institutes of Health, MD, USA, reported that these enzymes were inactivated by cysteine sulphinic acid formation when exposed to H2O2. But when H2O2 was removed, the peroxiredoxins were reactivated, although not to original levels. “The implication for cancer therapy is that peroxiredoxins could be used as a target”, says Rhee. “If peroxiredoxins are inhibited, some therapeutic agents may work more selectively”. Kathleen Nelson
Could dogs track down prostate cancer? Scientists at Cambridge University (UK) are looking for funding to see whether prostate cancer can be detected with some of the world’s most powerful olfactory array sensors – dogs’ noses. Dogs are currently used to detect earthquake and avalanche victims, drugs, and even minute quantities of explosives. The idea is to see whether this ability to pick out scents in complex olfactory environments can be exploited to detect prostate cancer signals in urine samples. “We have a substantial track record in describing the olfactory capacity of dogs—particularly their ability to discriminate between individual people, including identical twins”, explains Professor Don Broom, Cambridge Veterinary School. “The proposed pilot study would involve THE LANCET Oncology Vol 4 June 2003
training several animals to distinguish between urine samples from patients with malignant prostate cancer and those of healthy subjects. If the animals can detect some differentiating factor— whatever that may be—it could provide us with a very sensitive test for early diagnosis of the disease.” The idea has an intriguing history. In 1989, The Lancet reported the story of a dog that showed constant interest in a mole on its owner’s leg—once even trying to bite it off (Lancet 1989; 1: 734). When the owner eventually sought medical attention, the mole was diagnosed as melanoma. Indeed, reports exist that an American schnauzer was once successfully trained to detect melanomas. Another story reports a dog to have been constantly attracted to a lesion on its
owners’ skin—which turned out to be basal-cell carcinoma. “Certainly these are largely anecdotal reports”, says Broom, “but if dogs can do this, there could be great benefits from relatively little research.” If it works, trained dogs could some day be kept at training centres and urine samples sent out from hospitals for testing. “Such research could actually open many other doors”, commented Carlos Martínez-A (National Center for Biotechnology, Madrid, Spain). “If dogs can detect some marker of prostate cancer in urine, and then by experiment we can determine what that is, we might be able to develop a laboratory test for it. That is surely enough reason to give this a shot.” Adrian Burton
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
331
Courtesy of Z Wood
A new finding that links overexpression of peroxiredoxins—a group of enzymes that catalyse the reduction of oxidative substances—to apoptosis resistance in cancer cells suggests that inhibiting these enzymes may improve therapy. In bacteria, peroxiredoxins help the organism avoid degredation by their host through detoxification of hydrogen peroxide (H2O2). But, eukaryotic versions of the peroxiredoxins become inactivated by high concentrations of H2O2, enabling it to accumulate inside the cell. “Mammalian cells could easily have mutated to rid themselves of this sensitivity [to H2O2], but they didn’t”, says Zachary Wood, Oregon State University (USA). “So, we deduced that it must provide some advantage.” Wood and colleagues from Wake Forest University (NC, USA) came up with a theory called the floodgate hypothesis (Science 2003; 300: 650–53) to explain their findings. They believe peroxiredoxin inactivation constitutes a cellular switch, which enables mammalian cells to use H2O2 as a signalling molecule. In resting cells, large amounts of peroxiredoxins keep the concentration of H2O2 low, so it cannot
Differences between the prokaryotic (purple) and eukaryotic (yellow) forms of peroxiredoxin.
peroxiredoxin enzymes”, so H2O2 is free to accumulate in the cell. “Here, the floodgate appears too strong and remains unopened despite an H2O2 pulse”, he says. H2O2 can react with thiols on proteins involved in the NFB and
MAP kinase signalling pathways starting a chain of events that leads to apoptosis. “Some cancer cell lines overexpress peroxiredoxins and are therefore protected from killing by tumour necrosis factors and cisplatin”, which use H2O2 to activate apoptotic pathways, he adds. However, Wood and co-workers were puzzled by the observation that peroxiredoxin inactivation seemed to be irreversible. If this observation was correct, it would limit the effectiveness of any signalling system. But, a related paper published in the same issue of Science (2003; 300: 653–56) proves that the inactivation is reversible in vivo. Sue Goo Rhee and colleagues from the National Institutes of Health, MD, USA, reported that these enzymes were inactivated by cysteine sulphinic acid formation when exposed to H2O2. But when H2O2 was removed, the peroxiredoxins were reactivated, although not to original levels. “The implication for cancer therapy is that peroxiredoxins could be used as a target”, says Rhee. “If peroxiredoxins are inhibited, some therapeutic agents may work more selectively”. Kathleen Nelson
Could dogs track down prostate cancer? Scientists at Cambridge University (UK) are looking for funding to see whether prostate cancer can be detected with some of the world’s most powerful olfactory array sensors – dogs’ noses. Dogs are currently used to detect earthquake and avalanche victims, drugs, and even minute quantities of explosives. The idea is to see whether this ability to pick out scents in complex olfactory environments can be exploited to detect prostate cancer signals in urine samples. “We have a substantial track record in describing the olfactory capacity of dogs—particularly their ability to discriminate between individual people, including identical twins”, explains Professor Don Broom, Cambridge Veterinary School. “The proposed pilot study would involve THE LANCET Oncology Vol 4 June 2003
training several animals to distinguish between urine samples from patients with malignant prostate cancer and those of healthy subjects. If the animals can detect some differentiating factor— whatever that may be—it could provide us with a very sensitive test for early diagnosis of the disease.” The idea has an intriguing history. In 1989, The Lancet reported the story of a dog that showed constant interest in a mole on its owner’s leg—once even trying to bite it off (Lancet 1989; 1: 734). When the owner eventually sought medical attention, the mole was diagnosed as melanoma. Indeed, reports exist that an American schnauzer was once successfully trained to detect melanomas. Another story reports a dog to have been constantly attracted to a lesion on its
owners’ skin—which turned out to be basal-cell carcinoma. “Certainly these are largely anecdotal reports”, says Broom, “but if dogs can do this, there could be great benefits from relatively little research.” If it works, trained dogs could some day be kept at training centres and urine samples sent out from hospitals for testing. “Such research could actually open many other doors”, commented Carlos Martínez-A (National Center for Biotechnology, Madrid, Spain). “If dogs can detect some marker of prostate cancer in urine, and then by experiment we can determine what that is, we might be able to develop a laboratory test for it. That is surely enough reason to give this a shot.” Adrian Burton
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
331