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Inhibitor of MAP kinase activation blocks colon cancer growth
Gastroenterology News John H. Walsh, Section Editor inhibitor that was very effective against colon cancer cell lines was not effective against a leukemia cell line that did not express activated MAP kinase. The MEK antagonist markedly inhibited ctivation of a variety of receptors by growth of subcutaneously transplanted colon extracellular hormones and growth faccancers in mice in parallel with decreased tors leads to phosphorylation of MAP kinases MAP kinase activity in the tumors. Further ERK1 and ERK2 that in turn actitesting of PD 184352 in colon vate a variety of transcription cancer cells revealed that it had factors that stimulate cell funcadditional effects including detions including proliferation. The creased invasiveness and deenzyme that activates MAP kicreased angiogenesis, suggesting nases is known as MEK1 (MAP a decreased potential for metakinase kinase) and is part of a static spread. cascade stimulated by the protoThis potentially new agent oncogene ras. Because MEK is against colon cancer has not yet the only enzyme known to actientered clinical trials. Dr. Envate MAP kinases, it is a potential rique Rozengurt of the Univertarget for drugs that could inhibit sity of California Los Angeles feels tumor growth. that it may well be useful as an A group at Parke-Davis Pharanticancer drug but that toxicimaceutical Research led by Alan ties found with other antiproliferSaltiel and Judith S. Sebolt-Leoative agents used to treat cancer, pold reported in the July 1999 including bone marrow suppresissue of Nature Medicine encoursion and inhibition of gastrointesaging results with a newly develtinal mucosal growth are also oped MEK inhibitor used against likely for MEK antagonists. Howcultured and transplanted colon ever, because the target of PD cancer cell lines. The compound, 184352 is so different from those known as PD 184352, is a potent attacked by other classic chemoMEK inhibitor that is effective PD 184352, a potent, highly specific, and orally active inhibitor of MEK therapeutic agents (e.g., metaorally and that persists for at least (MAP kinase kinase) acts at a critical convergence point through which bolic pathways, DNA, and the 12 hours after a single dose. receptor tyrosine kinases (RTK) and G protein-coupled receptors (GPCR) machinery of cell division), it activate MAP kinase and stimulate multiple downstream effects including may turn out to be very useful for When given to cultured colon tumor cell proliferation. treatment of certain cancers eicancer cell lines it inhibited MAP ther alone or in combination. kinase phosphorylation, pre-
Inhibitor of MAP Kinase Activation Blocks Colon Cancer Growth
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UNOS, Feds Continue to Wrestle Over Liver Allocation he battle over how to allocate one of the nation’s scarcest medical resources has raged over the summer as the Institute of Medicine (IOM), at the request of Congress, drafted a report on how best to distribute donated livers for transplant, and the United Network for Organ Sharing (UNOS) announced a new policy designed to appease government concerns that the sickest patients are not always being given the highest priority. Both actions were taken in response to a Clinton Administration mandate that UNOS revamp its system so that organs are shared more broadly. The UNOS system, in place since passage of the National Organ Transplant Act in 1984, divides the nation into 62 local areas and 11 regions, with local recipients given the highest priority according to their severity of illness.
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vented cell cycle progression from the G1 to the S phase, and inhibited anchorage-independent growth. These actions were dose-dependent and reversible. Colon cancers are particularly likely to contain high levels of activated MAP kinase and therefore are good models to test the effects of MAP kinase inhibition. The MEK
The IOM panel recommended that organs be distributed to the sickest patients on a regional basis, with each region consisting of approximately 9 million people. Meanwhile, UNOS, after opposing the U.S. Department of Health and Human Services regulations for more than a year, approved a revised policy in which, if no match is found among the most urgent category of patients (Status 1) in the local area of the donor, the liver would be offered to Status 1 patients in the region where the donation occurred before being considered for less urgent local candidates. The new policy should decrease the waiting time for the sickest patients (who currently make up one-fifth of the liver transplant waiting list) from 4 to 2 days and increase the number of transplants performed for these patients by nearly 8%, according to the network. But UNOS also pointed out the negative aspects to the change: with repeat transplants
rising slightly, fewer livers may be available for all patients; because the chance of transplant failure is greater with sicker patients, the overall 1- and 3-year survival rates are expected to decrease slightly; and, perhaps most significantly, shipping livers greater distances increases the chance of organ rejection, because patients are far more likely to experience graft failure if the organ has been outside the body for more than 12 hours. ‘‘This change seeks to ensure that patients with acute liver failure, who have an extremely high mortality rate unless they’re transplanted promptly but can do very well following such a transplant, will have access to a larger number of potential organs in a shorter period of time,’’ says Dr. Paul Martin of the liver transplant program at UCLA. ‘‘Realistically, though, no system is going to be perfect, or satisfy everyone, as long as there continues to be a shortage of cadaveric donors.’’
GASTROENTEROLOGY 1999;117:523–524
Gastroenterology News continued
Results Pending on Secretin’s Benefits to Autism, But Many Aren’t Willing to Wait mong the most closely watched clinical trials of 1999 are the more than a dozen testing the effectiveness of treating autism with secretin, a drug that has been used for nearly 2 decades to diagnose pancreatic dysfunction. After highly publicized anecdotal reports of dramatic improvements in autistic children who had been administered the porcinederived compound, the National Institutes of Health quickly assembled two meetings late last year, out of which the first double-blind, placebo-controlled trials of the safety and efficacy of secretin in autism were launched. Several articles have already been submitted for publication, and a follow-up meeting to review data from the various trials will most likely be scheduled for early next year, according to Dr. Marie Bristol-Power, health scientist administrator at the National Institute of Child Health and Human Development. But, buoyed by network-TV coverage of a woman whose mostly mute autistic son began speaking after being prescribed secretin to test his pancreatic function, many parents of autistic children have chosen not to wait. Bristol-Power estimates that as many as 2000 children in the United States have been admin-
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New Tools to Study Motility and Satiety From the Receptor Orphanage he structure of G protein coupled receptors (GPCR) follows a general motif that includes 7 transmembrane domains and other characteristic features. Large-scale screening of cDNA libraries has yielded a number of
T
Erythromycin-Responsive Motilin Receptor Regulates Upper Gastrointestinal Motility he elusive motilin receptor was isolated by a group from Merck Research Laboratories led by Andrew Howard using a mass screening technique to find a ligand for an orphan receptor (GPR38) with a similarity to a
T
Melanin Concentrating Hormone Receptor Regulates Food Intake similar strategy was used by a group from SmithKline Beecham Pharmaceuticals led by Jon Chambers and by another group from University of California, Irvine led by Olivier
A 524
istered the drug off-label through a variety of sources, from gastroenterologists and pediatricians to family physicians, chiropractors, and, in some cases, the parents themselves. Although secretin has seemed to have a good safety profile since being FDA-approved for single-dose diagnostic use in the early 1980s, it is now being used in much higher doses than the recommended 1–2 clinical units per kg, and for more than 1 administration. Bristol-Power is hearing reports of doses as high as 8 cu/kg, and as many as 15 administrations. In the absence of data about the safety of using such high quantities of a drug derived from pig intestines that is only about 60% pure, her institute, as well as many other observers, are concerned about a possible public health crisis. One of the reasons for the high doses is that secretin is extremely scarce, since the only licensed U.S. manufacturer, Ferring Pharmaceuticals, has ceased producing the drug. ‘‘It’s difficult for parents to get, and because the product isn’t stable, parents feel that they have to use it all now or not at all,’’ says Bristol-Power. The scarcity is contributing to other concerns, including cost. Secretin, which wholesales for $179 a vial, has been hocked for thousands of dollars over the Internet, according to Bristol-Power. ‘‘People have literally called saying they’ve mortgaged their
homes to get this medicine for their children,’’ she says. Bristol-Power has also heard reports of bogus versions of secretin being sold. Assuming secretin is shown to be effective as a treatment for autism, one of the hopes is that a synthetic version will produce equal benefits. A synthetic product would have the dual benefit of relieving concerns about immunologic side effects and being able to be manufactured in unlimited doses, without the painstaking methods required by the biologic version. Both synthetic and biologic versions of secretin are being tested in the double-blind clinical trials, and early reports are that the results have been similar. As to the question of secretin’s efficacy in treating autism, Dr. Raun Melmed, director of the nonprofit Southwest Autism Research Center and codirector of one of the trials of synthetic secretin, says: ‘‘It is probably unlikely that there will be one silver bullet that will ever be able to address the complex symptoms of autism. At the same time, it is becoming more evident that the gut-brain connection is playing a significant role, at least in the symptoms that the children have, and possibly even in the etiology of the condition. For that reason, drugs, including secretin, that address the gut-brain connection will very possibly lead to improvement in their symptoms.’’
molecules that appear to be GPCR but have unknown ligands and functions. These molecules are called orphan receptors. One strategy to identify natural ligands for orphan receptors is to transfect them into cells and search for compounds that stimulate receptor mediated functions, such as increased intracellular calcium concentrations. This approach can be carried out with a large
battery of compounds until one is identified that produces a positive response. Further exploration of structurally related compounds can reveal the specificity of the receptor and possibly the native ligand. Recently this strategy has been successfully used to identify receptors for motilin and for melanin concentrating hormone (MCH).
known receptor for growth hormone secretagogues (reported in Science, June 25, 1999). Motilin, fragments of motilin, and erythromycin cause pharmacologically appropriate calcium responses in cells transfected with this receptor at doses similar to those that cause smooth muscle contraction in cells that express native motilin receptors. This orphan receptor thus was identified as the motilin receptor and given the name MTL-R1A.
The motilin receptor was localized in nerves that also contain nitric oxide, in a few that produce acetylcholine, as well as in some smooth muscle cells in the gut. The availability of probes for this receptor will facilitate further studies of the physiology of motilin and will simplify development of drugs related to erythromycin that can be used to increase upper gastrointestinal motility.
Civelli to identify the ligand for an orphan receptor resembling secretin receptors known as SLC-1 as melanin concentrating hormone (reported in Nature, July 15, 1999). MCH is a 19 amino acid peptide found in the hypothalamus. It stimulates feeding behavior when injected into the brain, is up-regulated in genetically obese mice and fasted animals, is down-regulated by leptin, and mice lacking
MCH are lean and have decreased food intake. Thus, MCH seems to be a physiological stimulant of feeding behavior, and its receptor should be a good target for drugs designed to decrease food intake. Stories by Dan Gordon The section editor can be sent suggestions for articles at [email protected]
Inhibitor of MAP Kinase Activation Blocks Colon Cancer Growth
A
UNOS, Feds Continue to Wrestle Over Liver Allocation he battle over how to allocate one of the nation’s scarcest medical resources has raged over the summer as the Institute of Medicine (IOM), at the request of Congress, drafted a report on how best to distribute donated livers for transplant, and the United Network for Organ Sharing (UNOS) announced a new policy designed to appease government concerns that the sickest patients are not always being given the highest priority. Both actions were taken in response to a Clinton Administration mandate that UNOS revamp its system so that organs are shared more broadly. The UNOS system, in place since passage of the National Organ Transplant Act in 1984, divides the nation into 62 local areas and 11 regions, with local recipients given the highest priority according to their severity of illness.
T
vented cell cycle progression from the G1 to the S phase, and inhibited anchorage-independent growth. These actions were dose-dependent and reversible. Colon cancers are particularly likely to contain high levels of activated MAP kinase and therefore are good models to test the effects of MAP kinase inhibition. The MEK
The IOM panel recommended that organs be distributed to the sickest patients on a regional basis, with each region consisting of approximately 9 million people. Meanwhile, UNOS, after opposing the U.S. Department of Health and Human Services regulations for more than a year, approved a revised policy in which, if no match is found among the most urgent category of patients (Status 1) in the local area of the donor, the liver would be offered to Status 1 patients in the region where the donation occurred before being considered for less urgent local candidates. The new policy should decrease the waiting time for the sickest patients (who currently make up one-fifth of the liver transplant waiting list) from 4 to 2 days and increase the number of transplants performed for these patients by nearly 8%, according to the network. But UNOS also pointed out the negative aspects to the change: with repeat transplants
rising slightly, fewer livers may be available for all patients; because the chance of transplant failure is greater with sicker patients, the overall 1- and 3-year survival rates are expected to decrease slightly; and, perhaps most significantly, shipping livers greater distances increases the chance of organ rejection, because patients are far more likely to experience graft failure if the organ has been outside the body for more than 12 hours. ‘‘This change seeks to ensure that patients with acute liver failure, who have an extremely high mortality rate unless they’re transplanted promptly but can do very well following such a transplant, will have access to a larger number of potential organs in a shorter period of time,’’ says Dr. Paul Martin of the liver transplant program at UCLA. ‘‘Realistically, though, no system is going to be perfect, or satisfy everyone, as long as there continues to be a shortage of cadaveric donors.’’
GASTROENTEROLOGY 1999;117:523–524
Gastroenterology News continued
Results Pending on Secretin’s Benefits to Autism, But Many Aren’t Willing to Wait mong the most closely watched clinical trials of 1999 are the more than a dozen testing the effectiveness of treating autism with secretin, a drug that has been used for nearly 2 decades to diagnose pancreatic dysfunction. After highly publicized anecdotal reports of dramatic improvements in autistic children who had been administered the porcinederived compound, the National Institutes of Health quickly assembled two meetings late last year, out of which the first double-blind, placebo-controlled trials of the safety and efficacy of secretin in autism were launched. Several articles have already been submitted for publication, and a follow-up meeting to review data from the various trials will most likely be scheduled for early next year, according to Dr. Marie Bristol-Power, health scientist administrator at the National Institute of Child Health and Human Development. But, buoyed by network-TV coverage of a woman whose mostly mute autistic son began speaking after being prescribed secretin to test his pancreatic function, many parents of autistic children have chosen not to wait. Bristol-Power estimates that as many as 2000 children in the United States have been admin-
A
New Tools to Study Motility and Satiety From the Receptor Orphanage he structure of G protein coupled receptors (GPCR) follows a general motif that includes 7 transmembrane domains and other characteristic features. Large-scale screening of cDNA libraries has yielded a number of
T
Erythromycin-Responsive Motilin Receptor Regulates Upper Gastrointestinal Motility he elusive motilin receptor was isolated by a group from Merck Research Laboratories led by Andrew Howard using a mass screening technique to find a ligand for an orphan receptor (GPR38) with a similarity to a
T
Melanin Concentrating Hormone Receptor Regulates Food Intake similar strategy was used by a group from SmithKline Beecham Pharmaceuticals led by Jon Chambers and by another group from University of California, Irvine led by Olivier
A 524
istered the drug off-label through a variety of sources, from gastroenterologists and pediatricians to family physicians, chiropractors, and, in some cases, the parents themselves. Although secretin has seemed to have a good safety profile since being FDA-approved for single-dose diagnostic use in the early 1980s, it is now being used in much higher doses than the recommended 1–2 clinical units per kg, and for more than 1 administration. Bristol-Power is hearing reports of doses as high as 8 cu/kg, and as many as 15 administrations. In the absence of data about the safety of using such high quantities of a drug derived from pig intestines that is only about 60% pure, her institute, as well as many other observers, are concerned about a possible public health crisis. One of the reasons for the high doses is that secretin is extremely scarce, since the only licensed U.S. manufacturer, Ferring Pharmaceuticals, has ceased producing the drug. ‘‘It’s difficult for parents to get, and because the product isn’t stable, parents feel that they have to use it all now or not at all,’’ says Bristol-Power. The scarcity is contributing to other concerns, including cost. Secretin, which wholesales for $179 a vial, has been hocked for thousands of dollars over the Internet, according to Bristol-Power. ‘‘People have literally called saying they’ve mortgaged their
homes to get this medicine for their children,’’ she says. Bristol-Power has also heard reports of bogus versions of secretin being sold. Assuming secretin is shown to be effective as a treatment for autism, one of the hopes is that a synthetic version will produce equal benefits. A synthetic product would have the dual benefit of relieving concerns about immunologic side effects and being able to be manufactured in unlimited doses, without the painstaking methods required by the biologic version. Both synthetic and biologic versions of secretin are being tested in the double-blind clinical trials, and early reports are that the results have been similar. As to the question of secretin’s efficacy in treating autism, Dr. Raun Melmed, director of the nonprofit Southwest Autism Research Center and codirector of one of the trials of synthetic secretin, says: ‘‘It is probably unlikely that there will be one silver bullet that will ever be able to address the complex symptoms of autism. At the same time, it is becoming more evident that the gut-brain connection is playing a significant role, at least in the symptoms that the children have, and possibly even in the etiology of the condition. For that reason, drugs, including secretin, that address the gut-brain connection will very possibly lead to improvement in their symptoms.’’
molecules that appear to be GPCR but have unknown ligands and functions. These molecules are called orphan receptors. One strategy to identify natural ligands for orphan receptors is to transfect them into cells and search for compounds that stimulate receptor mediated functions, such as increased intracellular calcium concentrations. This approach can be carried out with a large
battery of compounds until one is identified that produces a positive response. Further exploration of structurally related compounds can reveal the specificity of the receptor and possibly the native ligand. Recently this strategy has been successfully used to identify receptors for motilin and for melanin concentrating hormone (MCH).
known receptor for growth hormone secretagogues (reported in Science, June 25, 1999). Motilin, fragments of motilin, and erythromycin cause pharmacologically appropriate calcium responses in cells transfected with this receptor at doses similar to those that cause smooth muscle contraction in cells that express native motilin receptors. This orphan receptor thus was identified as the motilin receptor and given the name MTL-R1A.
The motilin receptor was localized in nerves that also contain nitric oxide, in a few that produce acetylcholine, as well as in some smooth muscle cells in the gut. The availability of probes for this receptor will facilitate further studies of the physiology of motilin and will simplify development of drugs related to erythromycin that can be used to increase upper gastrointestinal motility.
Civelli to identify the ligand for an orphan receptor resembling secretin receptors known as SLC-1 as melanin concentrating hormone (reported in Nature, July 15, 1999). MCH is a 19 amino acid peptide found in the hypothalamus. It stimulates feeding behavior when injected into the brain, is up-regulated in genetically obese mice and fasted animals, is down-regulated by leptin, and mice lacking
MCH are lean and have decreased food intake. Thus, MCH seems to be a physiological stimulant of feeding behavior, and its receptor should be a good target for drugs designed to decrease food intake. Stories by Dan Gordon The section editor can be sent suggestions for articles at [email protected]