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Tricyclic antidepressants, first developed in the 1950s, are no longer in wide use. But the results of a recent study by a research team at Stanford University (Stanford, CA, USA) could well give them a new lease of life—not for depression, but for small-cell lung cancer. The team have discovered that the tricyclic antidepressant imipramine can curb the growth of human small-cell lung cancers in mice and tumour cell cultures. The drug killed nearly 100% of the tumour cells in culture. “The cell death was very evident in culture—a very clear, rapid, and potent effect”, Julien Sage, Associate Professor in the departments of paediatrics and genetics at Stanford University School of Medicine and one of the two senior coauthors of the report, told The Lancet Respiratory Medicine. There was also a clear effect on the human tumours grafted into mice, he added. “The drug slowed or blocked tumour growth, not only of the primary tumours, but also the metastases that had developed in about 50% of the mice.” The curbing effect was also seen in mice resistant to traditional chemotherapy. The researchers believe that the drug kills the tumour cells by activating a self-destruct pathway normally inactive in such cells. They have begun recruiting patients for a phase 2A (dose escalation) clinical trial of desipramine, an antidepressant similar to imipramine in molecular structure and tumour cell killing effect, but with fewer side-effects. How, one might ask, did the research team hit on this outdated antidepressant as a potential anticancer drug? Not by serendipity, but by a method devised by a team led by Atul Butte, the other senior coauthor of the report and division chief and Associate Professor at Stanford
University School of Medicine. Butte explains: “We used our custom-built computer program to scan publicly available databases containing information on thousands of drugs and drug candidates developed for any purpose, as well as databases containing hundreds of thousands of gene expression profiles of healthy and disease states. We asked the programme to find drug–disease matches where gene expression profiles and disease profiles cancelled each other out. So, if we find that the disease we’re interested in increases the expression of certain genes, we look for a drug likely to lower gene expression and therefore to counter the disease, whatever the original target of the drug or cause of the disease.” In the Stanford study, imipramine topped the list of possible candidates. This study is an example of drug repositioning, also known as drug repurposing. The principle is not new. One of the earliest examples is mustard gas, first used as a weapon of war, but later found to possess anticancer properties. Other early examples include minoxidil, repositioned from hypertension to baldness; sildenafil citrate (Viagra), from heart disease to erectile dysfunction; and thalidomide, from a sedative to a treatment for leprosy and multiple myeloma. Examples from respiratory medicine include the antidepressant bupropion, now used for smoking cessation. Probenecid, a uricosuric drug, is being explored for its potential against influenza A. Preclinical research is in progress to investigate the antihypertensive benzthiazide for use against squamous-cell lung carcinoma, and the antiparkinsonian drug entacapone against multidrugresistant tuberculosis. Research is
www.thelancet.com/respiratory Vol 1 November 2013
also underway into several drugs that could be repurposed to correct the immune defects of cystic fibrosis. Early repositioning efforts relied mainly on serendipity and trial and error. But in recent years the practice has burgeoned into a hightech discipline, with sophisticated methods used to run systematic searches for drugs that could be investigated in new targets. A major driver of this repositioning boom is the time and cost needed to take a traditional drug through the development process. As Butte remarks: “It typically takes more than a decade and more than a billion [US] dollars to translate a laboratory finding into a successful drug. With our methodology, we should be able to cut that time substantially, and vastly reduce the cost.” Much of the saving is due to the fact that repositioned drugs will have already been approved for safety. Public health institutions in several countries have also entered the repositioning arena. In the USA, for example, the National Center for Advancing Translational Sciences (part of the National Institutes of Health) is collaborating with eight major pharmaceutical companies that have agreed to make 58 compounds available for potential repositioning as treatments for eight diseases, including the rare lung disease lymphangioleiomyomatosis. The Center plans to provide funds of up to $20 million over 3 years for this repositioning research. With roughly 7000 rare diseases that affect millions worldwide and that for the most part lack effective treatment, there is little doubt that the world’s drug repositioners will have their hands full for some time to come.
Science Photo Library
Teaching old drugs new tricks raises hopes of new treatment for lung cancer
Published Online October 17, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70196-6 For the drug repositioning study see Cancer Discov 2013; published online Sept 23. DOI:10.1158/2159-8290.CD-130183
John Maurice 677
Tricyclic antidepressants, first developed in the 1950s, are no longer in wide use. But the results of a recent study by a research team at Stanford University (Stanford, CA, USA) could well give them a new lease of life—not for depression, but for small-cell lung cancer. The team have discovered that the tricyclic antidepressant imipramine can curb the growth of human small-cell lung cancers in mice and tumour cell cultures. The drug killed nearly 100% of the tumour cells in culture. “The cell death was very evident in culture—a very clear, rapid, and potent effect”, Julien Sage, Associate Professor in the departments of paediatrics and genetics at Stanford University School of Medicine and one of the two senior coauthors of the report, told The Lancet Respiratory Medicine. There was also a clear effect on the human tumours grafted into mice, he added. “The drug slowed or blocked tumour growth, not only of the primary tumours, but also the metastases that had developed in about 50% of the mice.” The curbing effect was also seen in mice resistant to traditional chemotherapy. The researchers believe that the drug kills the tumour cells by activating a self-destruct pathway normally inactive in such cells. They have begun recruiting patients for a phase 2A (dose escalation) clinical trial of desipramine, an antidepressant similar to imipramine in molecular structure and tumour cell killing effect, but with fewer side-effects. How, one might ask, did the research team hit on this outdated antidepressant as a potential anticancer drug? Not by serendipity, but by a method devised by a team led by Atul Butte, the other senior coauthor of the report and division chief and Associate Professor at Stanford
University School of Medicine. Butte explains: “We used our custom-built computer program to scan publicly available databases containing information on thousands of drugs and drug candidates developed for any purpose, as well as databases containing hundreds of thousands of gene expression profiles of healthy and disease states. We asked the programme to find drug–disease matches where gene expression profiles and disease profiles cancelled each other out. So, if we find that the disease we’re interested in increases the expression of certain genes, we look for a drug likely to lower gene expression and therefore to counter the disease, whatever the original target of the drug or cause of the disease.” In the Stanford study, imipramine topped the list of possible candidates. This study is an example of drug repositioning, also known as drug repurposing. The principle is not new. One of the earliest examples is mustard gas, first used as a weapon of war, but later found to possess anticancer properties. Other early examples include minoxidil, repositioned from hypertension to baldness; sildenafil citrate (Viagra), from heart disease to erectile dysfunction; and thalidomide, from a sedative to a treatment for leprosy and multiple myeloma. Examples from respiratory medicine include the antidepressant bupropion, now used for smoking cessation. Probenecid, a uricosuric drug, is being explored for its potential against influenza A. Preclinical research is in progress to investigate the antihypertensive benzthiazide for use against squamous-cell lung carcinoma, and the antiparkinsonian drug entacapone against multidrugresistant tuberculosis. Research is
www.thelancet.com/respiratory Vol 1 November 2013
also underway into several drugs that could be repurposed to correct the immune defects of cystic fibrosis. Early repositioning efforts relied mainly on serendipity and trial and error. But in recent years the practice has burgeoned into a hightech discipline, with sophisticated methods used to run systematic searches for drugs that could be investigated in new targets. A major driver of this repositioning boom is the time and cost needed to take a traditional drug through the development process. As Butte remarks: “It typically takes more than a decade and more than a billion [US] dollars to translate a laboratory finding into a successful drug. With our methodology, we should be able to cut that time substantially, and vastly reduce the cost.” Much of the saving is due to the fact that repositioned drugs will have already been approved for safety. Public health institutions in several countries have also entered the repositioning arena. In the USA, for example, the National Center for Advancing Translational Sciences (part of the National Institutes of Health) is collaborating with eight major pharmaceutical companies that have agreed to make 58 compounds available for potential repositioning as treatments for eight diseases, including the rare lung disease lymphangioleiomyomatosis. The Center plans to provide funds of up to $20 million over 3 years for this repositioning research. With roughly 7000 rare diseases that affect millions worldwide and that for the most part lack effective treatment, there is little doubt that the world’s drug repositioners will have their hands full for some time to come.
Science Photo Library
Teaching old drugs new tricks raises hopes of new treatment for lung cancer
Published Online October 17, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70196-6 For the drug repositioning study see Cancer Discov 2013; published online Sept 23. DOI:10.1158/2159-8290.CD-130183
John Maurice 677
