New research shows that the erectile dysfunction drug, tadalafil, may be an effective adjunct therapy for patients with pulmonary arterial hypertension (PAH). Italian researchers randomized 405 patients with PAH, of whom 53 percent were taking concomitant bosentan, to two study arms. The groups received either tadalafil or placebo orally once daily as monotherapy or as add-on therapy to bosentan. Compared with placebo, tadalafil, 40 mg, increased 6-minute walk distance, delayed the time to clinical worsening, and improved six of the eight short form (SF)-36 domains. In addition, tadalafil, 40 mg, increased cardiac output and reduced pulmonary artery pressures and pulmonary vascular resistance compared with baseline. Discontinuation due to adverse events was low (11 percent for tadalafil vs. 16 percent for placebo). Researchers conclude that tadalafil may provide an effective oral, once-daily therapy that can be combined with bosentan therapy for patients with PAH.

Asthma sufferers who regularly take the beta2-agonist formoterol are more likely to suffer non-fatal serious adverse events than those given placebos.  A review carried out by Cochrane Researchers showed a significantly increased risk for people who took the drug once or twice daily for at least 12 weeks.

Long-acting beta2-agonists are inhaled to help open the airways and last for 12 hours or more, but their long-term use is controversial.  Recent research has cast doubt on the safety of salmeterol.  Now researchers are calling into question the safety of the related drug formoterol.

“Our findings are similar to those of a review published earlier this year, which found that regular salmeterol causes an increase in non-fatal adverse events,” says lead researcher of both studies, Christopher Cates, who works in Community Health Sciences at St George’s, London.

22 studies involving 8,032 people diagnosed with asthma were included in the latest review.  In those studies that compared formoterol to a placebo, 16 patients per thousand taking formoterol suffered serious adverse effects, whilst only 10 per thousand taking placebos were similarly affected.  Serious adverse effects were most commonly asthma–related.  The increase in adverse events was more marked in younger patients.

“It is possible that children are at a higher risk of suffering serious effects due to this drug, but we can’t say for sure.  We would urge that all serious adverse events are more fully reported in medical journals so that we can make a better assessment of drug safety,” says Cates.

A Northwestern University research team has developed a promising nanomaterial-based biomedical device that could be used to deliver chemotherapy drugs locally to sites where cancerous tumors have been surgically removed.

The flexible microfilm device, which resembles a piece of plastic wrap and can be customized easily into different shapes, has the potential to transform conventional treatment strategies and reduce patients’ unnecessary exposure to toxic drugs.  The device takes advantage of nanodiamonds, an emergent technology, for sustained drug release.

The researchers demonstrated that the device releases the chemotherapy agent Doxorubicin in a sustained and consistent manner -a requirement of any implanted device for localized chemotherapy.  The results of the study are published online today (Oct.  2) by the journal ACS Nano.

“The thin device -a sort of blanket or patch -could be used to treat a localized region where residual cancer cells might remain after a tumor is removed,” said Dean Ho, assistant professor of biomedical engineering and mechanical engineering at Northwestern’s McCormick School of Engineering and Applied Science, who led the research.

If a surgical oncologist, for example, was removing a tumor from the breast or brain, the device could be implanted in the affected area as part of the same surgery.  This approach, which confines drug release to a specific location, could mitigate side effects and complications from other chemotherapy treatments.

“Several surgeons at Northwestern’s Feinberg School of Medicine, as well as other medical schools and hospitals, are very interested in the device because it is biocompatible and provides such stable and consistent drug release,” said Ho, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

In their study, Ho and his colleagues embedded millions of tiny drug-carrying nanodiamonds in the FDA-approved polymer parylene.  Currently used as a coating for implants, the biostable parylene is a flexible and versatile material resembling plastic wrap.  A substantial amount of drug can be loaded onto clusters of nanodiamonds, which have a high surface area.  The nanodiamonds then are put between extremely thin films of parylene, resulting in a device that is minimally invasive.

To test the device’s drug release performance, the researchers used Doxorubicin, a chemotherapeutic used to treat many types of cancer.  They found the drug slowly and consistently released from the embedded nanodiamond clusters for one month, with more Doxorubicin in reserve, indicating a more prolonged release (several months and longer) was possible.  The device also avoided the “burst” or massive initial release of the drug, a common disadvantage with conventional therapy.

In control experiments, where the drug was present but without the nanodiamonds, virtually all of the drug was released within one day.  By adding the drug-laden nanodiamonds to the device, drug release was instantly lengthened to the months-long timescale.

In addition to their large surface area, nanodiamonds have many other advantages that can be utilized in drug delivery.  They can be functionalized with nearly any type of therapeutic.  They can be suspended easily in water, which is important for biomedical applications.  The nanodiamonds, each being four to six nanometers in diameter, are minimally invasive to cells, biocompatible and do not cause inflammation, a serious complication.  And they are very scalable and can be produced in large quantities.

The architecture of the device is amenable to housing small molecule, protein, antibody or RNAor DNA-based therapeutics.  This gives the technology the potential to impact a range of treatment strategies where implanted, long-term drug release is needed.

Ho and his research group previously pioneered the application of nanodiamonds for systemic drug-carrying applications.  This new work successfully transitions the nanodiamonds from basic materials to serving as a foundation for device manufacturing.

To build the biomedical device, the researchers developed a streamlined approach where a double layer of parylene was fabricated, with the nanodiamond-drug complexes sandwiched in between.  The bottom layer, approximately 20 to 30 microns thick, serves as the backbone of the device, allowing it to be easily handled.  For the top layer, the research team created a thinner semi-porous film that allows the drug to slowly release from the device.

“One of the most significant aspects of this work is that the fabrication procedures are highly scalable, meaning hundreds, or even thousands, of devices potentially could be manufactured in parallel and at low cost,” said Ho.

“The nanodiamonds are quite economical and have already been mass-produced as lubrication components for automobiles and for use in electronics,” added Robert Lam, a graduate student in Ho’s research group and the article’s lead author.

In the area of localized chemotherapy, the team hopes that this technology will bring new levels of treatment efficacy that can complement injected chemotherapy to reduce dosages and decrease devastating side effects.

Because of the proven biocompatibility and massively parallel deposition capabilities of parylene, the researchers are engaged with pre-clinical trials of the nanodiamond-embedded parylene.

A UC Riverside-led team of biomedical scientists has found that a readily available drug called minocycline, used widely to treat acne and skin infections, can be used to treat Fragile X syndrome, the most common inherited cause of mental impairment and the most common cause of autism.

The study’s findings have already impacted future therapies, with the approval of a new clinical trial in Toronto, Canada, that will test minocycline in patients with Fragile X.

Neurons in the brain communicate with each other at specialized contact sites called synapses, with many of these synapses occurring on small mushroom-shaped structures called dendritic spines.

During early development dendritic spines have immature finger-like shapes.  But learning stabilizes the synapses and dendritic spines take on a mature mushroom shape, which make them more efficient.

The brains of patients with Fragile X syndrome have an overabundance of immature dendritic spines.

In their report, the researchers, led by Iryna Ethell and Douglas Ethell, faculty members in UCR’s Division of Biomedical Sciences, describe how dendritic spine development in mice with Fragile X is delayed by enzymes called matrix metalloproteinases (MMPs), which are involved in normal brain development and physiological processes.  They report that high levels of certain MMPs keep the synapses immature and inefficient.

But minocycline, they found, reduces these MMP levels in the mice, allowing the synapses to mature and make more efficient contacts between neurons in the brain.  The outcome: corrected brain abnormalities in dendritic spines, reduced anxiety and improved cognitive function.

Study results appear online, ahead of print, in the Journal of Medical Genetics.

In their experiments, the Ethells found that young Fragile X mice treated with minocycline showed an increase of dendritic spine maturation in the hippocampus, a brain area that is critical for learning and memory.  Besides less anxiety, minocycline-treated mice showed better exploration skills as compared to untreated mice.

The Ethells are enthusiastic about how their discovery already is leading to a clinical trial.

“Clinical studies often quickly follow such basic science because once there is a solid understanding of how problems arise, it is much easier to come up with solutions,” said Iryna Ethell, an associate professor of biomedical sciences.

The study was funded by a grant from the FRAXA Research Foundation.  FRAXA was founded in 1994 by three parents of children with Fragile X to support scientific research aimed at finding a treatment and a cure for Fragile X.

Dr. Michael Tranfaglia, FRAXA’s chief scientific officer, said of the UCR researchers, “This group has done something unique and incredibly valuable: They have identified an off-the-shelf treatment for Fragile X through their basic research.  By bringing their unique perspective to Fragile X research, they have helped us to understand why neurons are malformed in this disorder, and more importantly, how we can treat it.

“We were so impressed with their work that we just awarded Dr. Iryna Ethell the FRAXA Breakthrough Award for 2008.  This is easily the most important scientific breakthrough in the Fragile X field in many years.”

According to Dr. Carl Paribello, president of Fragile X Research Foundation of Canada and the director of the clinical trial (scheduled for early 2009) at Surrey Place Centre Fragile X Clinic in Toronto, Canada, the UCR-led study “will go a long way towards dispelling the idea that mental impairment cannot be treated.”

“The work could lead to the first treatment that actually targets the underlying defect in Fragile X syndrome and not just the symptoms,” Dr. Paribello said.

UCR’s Douglas Ethell, an assistant professor of biomedical sciences, noted that effective therapies for Fragile X syndrome are few and far between.  “This is a good time for identifying highly effective therapeutic strategies that might work in Fragile X patients,” he said.  “We are excited that our research has the potential to affect many lives.”

Fragile X affects 1 in 4000 males and 1 in 6000 females of all races and ethnic groups.  About 1 in 259 women carry Fragile X and could pass it to their children.  About 1 in 800 men carry Fragile X; their daughters will also be carriers.

Minocycline belongs to a group of antibiotics that has been used in people for more than fifty years to treat Lyme disease, acne, and other skin infections.

Minocycline may have beneficial effects in other disorders where higher-than-normal brain levels of MMP-9 are found.  It is currently under study for treating rheumatoid arthritis, multiple sclerosis (MS), Parkinson’s disease, and several other neurodegenerative conditions.

“In the future, new compounds that more specifically target MMP-9 can be developed and tested,” Douglas Ethell said.

Next in their research, the Ethells and their colleagues plan to refine the therapeutic strategy in Fragile X mice to determine the optimal age, if any, to administer minocycline.  They will also explore other MMP inhibitors that may be more effective than minocycline.

“We will investigate whether a combination of MMP inhibitors with other drugs, such as fenobam, can help mature the synapses in Fragile X mice,” Iryna Ethell said.

In the nucleus, DNA wraps around histone proteins, which pack the DNA and makes it less accessible for transcription. Many transcriptional activators promote histone acetylation, which opens the chromatin structure and helps recruit transcription machinery to the newly accessible genes. Conversely, some gene repressors promote deacetylation of histones. Because drug dependence is mediated partly by changes in gene expression, inhibitors of histone acetylation and deacetylation might prevent the development of drug dependence. Romieuet al. support this hypothesis by showing that administering histone deacetylase inhibitors shortly before giving rats access to cocaine reduced cocaine self-administration and decreased the number of times a rat poked its nose in a hole to receive a dose of cocaine. When rats receive cocaine daily, their response to a dose increases over time. This increased responsiveness, called sensitization, is thought to promote dependence. Cocaine sensitization is prevented by histone deacetylase inhibitors, suggesting inhibitors may effectively reduce dependence.

A surprising interaction may enable development of new HIV treatment strategies by exploiting infection with multiple pathogens.  The research, published by Cell Press in the September 11th issue of the journal Cell Host and Microbe, demonstrates that a drug commonly used to treat herpes directly suppresses HIV in coinfected tissues and thus may be beneficial for patients infected with both viruses.

Commonly, individuals infected with HIV are infected also with other microbes.  Infection with human herpesvirus (HHV), especially with herpes simplex virus-2 (HSV-2), is often associated with HIV.  These HHV infections may be either active or dormant, but HIV infection makes HHV reactivation more likely.

For many years, acyclovir (ACV), a well-studied drug, has been used safely to treat HHV in humans.  “HHV has a unique ability to phosphorylate ACV to activate it, making the drug quite specific for HHV and, for the same reason, relatively non-active against other viruses, including HIV,” offers senior study author Dr. Leonid Margolis from the National Institute of Health.  Nevertheless, some patients coinfected with HIV and HSV-2 exhibit lower HIV levels after ACV treatment.

“We decided to investigate this phenomenon experimentally using small blocks of human tissues” says Dr. Margolis.  “Drs.  Andrea Lisco and Christophe Vanpouille who performed this work in my laboratory found that although ACV doesn’t inhibit HIV in ’sterile’ cell lines, it does, surprisingly, suppress HIV in tissues that carry no HSV-2 but various other HHVs.”  In collaboration with a prominent AIDS researcher Dr. Raymond Schinazi from Emory University and Dr. Matthias Gotte from McGill University, the researchers found that phosphorylated ACV that is formed in HHV-infected cells directly inhibits the HIV-1 reverse transcriptase (RT), thus preventing HIV from copying itself.

These results not only help to explain the response to ACV seen in patients coinfected with HSV-2 and HIV, but also suggest that ACV may be used against HIV in patients infected with various other HHVs, including the low-pathogenic and ubiquitous HHV-6 and HHV-7.  Moreover, in collaboration with Drs.  Balzarini from Catholic University of Leuven and McGuigan from Cardiff University, Dr. Margolis and his team demonstrated that new strategies for development of novel HIV inhibitors based on ACV structure can now be developed.  “We provide definitive experimental evidence of inhibition of HIV-1 RT activity by phosphorylated ACV and demonstrate that ACV phosphorylation occurring in human tissues infected by various HHVs transforms this widely-used inexpensive anti-herpes drug into a direct HIV inhibitor,” concludes Dr. Margolis.

A drug used to increase blood production in both medical treatments and athletic doping scandals seems also to improve memory in those using it.  New research published in the open access journal BMC Biology shows that the memory enhancing effects of erythropoietin (EPO) are not related to its effects on blood production but due to direct influences on neurons in the brain.  The findings may prove useful in the treatment of diseases affecting brain function, such as schizophrenia, multiple sclerosis, and Alzheimer’s.

Patients given EPO to treat chronic kidney failure had been observed to have improved cognition after starting the drug.  “These effects of EPO were thought to result from the blood-boosting effects of the drug”, explains Hannelore Ehrenreich at the Max Planck Institute, “but the finding of receptors for EPO on nerve cells in the brain suggests that some other mechanism might be involved.”

To investigate the mechanisms of EPO-enhanced cognition, the researchers injected mice with EPO every other day for three weeks (11 doses) to test the effects of long-term exposure.  After the treatment period, mice given EPO had better memory in some situations than did mice that had been given a placebo instead.  The improvement in memory lasted up to three weeks from the last EPO dose and outlasted increased blood-cell production, but had disappeared by four weeks.  Mice given three doses saw no benefit with respect to memory improvement.

“Young mice systematically treated with EPO for three weeks have improved memory, similar to the dramatic improvements observed in endurance and muscular performance athletes who use EPO to boost performance”, says Ehrenreich.  The specific memory improvements were associated with the hippocampus, a structure in the brain involved in learning and memory, among other functions.

The researchers did a series of experiments on hippocampal tissue taken from the mice and found that EPO directly affected the neurons in this structure.  “EPO had pronounced effects on short-term and long-term plasticity in the hippocampus as well as on synaptic transmission”, the researchers report.  “Treatment with EPO seems to increase the number of inhibitory circuits, which actually increases the efficiency of transmission of excitatory nerve impulses in specific neurons, resulting in greater short-term and long-term plasticity in memory pathways in the hippocampus.”

These findings begin to shed light on the mechanisms of improvements in cognition seen in patients with schizophrenia and multiple sclerosis as a result of treatment with this drug.  As well as working to refine these findings, further studies might also investigate the effects of EPO on other brain regions that might be associated with improvements in motor functions in multiple sclerosis, and investigate the potential of using EPO or targeting the networks involved in EPO-generated neuronal plasticity in the treatment of neurodegenerative diseases.

Laboratories that perform pre-employment drug screening are fighting back — against hundreds of products now on the market that promise to mask evidence of illicit drug use, according to an article scheduled for the Sept. 8 issue of Chemical & Engineering News, ACS’ weekly newsmagazine.

In the article, C&EN Senior Business Editor Melody Voith points out that job applicants now have access to an array of products purported to alter urine samples to hide evidence of marijuana, cocaine, and other illegal drugs.  Some are supposed to dilute evidence of illicit drugs to levels undetectable by conventional tests.  Others used adulterants advertised to inactivate or destroy chemical markers used to identify drugs.

Drug-testers are responding with more sensitive tests that can identify tell-tale chemical signs of diluted urine samples or quickly detect the presence of adulterants.  The article also explains that testers may get a boost from proposed new drug testing guidelines from the U.S. Department of Health & Human Services.  They would permit use of hair and saliva samples in drug screening of candidates for federal jobs.  That screening could indentify illicit drugs more reliably than urine samples alone, the article notes.

Researchers in Florida are reporting an advance toward tapping the enormous potential of an emerging new group of antibiotics identical to certain germ-fighting proteins found in the human immune system.  Their study, which may help fight the growing epidemic of drug-resistant infections, is in the current (August) issue of ACS’ Biomacromolecules, a monthly journal.

In the new study, D. Matthew Eby, Glenn Johnson, and Karen Farrington point out that scientists have long eyed the germ-fighting potential of antimicrobial peptides (AMPs).  These small proteins fight a wide range of bacteria and fungi in the body and have the potential to be developed into powerful drugs to overcome infections that are resistant to conventional drugs.  But scientists report difficulty producing effective AMPs because the antibiotics are fragile and easily destroyed in the body.  An effective way to stabilize them is needed, they say.

In laboratory studies, the researchers showed that the coating protected the antibiotics from destruction by other chemicals while allowing the release of a controlled antibiotic dose for an extended period of time.  These features are key to the effective use of AMPs as antibiotics, they say.

Substances in marijuana show promise for fighting deadly drug-resistant bacterial infections, including so-called “superbugs,” without causing the drug’s mood-altering effects, scientists in Italy and the United Kingdom are reporting.  Besides serving as infection-fighting drugs, the substances also could provide a more environmentally-friendly alternative to synthetic antibacterial substances now widely used in personal care items, including soaps and cosmetics, they say.  Their study is scheduled for the Sept. 26 issue of ACS’ monthly Journal of Natural Products.

In the new study, Giovanni Appendino and colleagues point out that scientists have known for years that marijuana contains antibacterial substances.  However, little research has been done on those ingredients, including studies on their ability to fight antibiotic resistant infections, the scientists say.

To close that gap, researchers tested five major marijuana ingredients termed cannabinoids on different strains of methicillin-resistant Staphylococcus aureus (MRSA), a “superbug” increasingly resistant to antibiotics.  All five substances showed potent germ-killing activity against these drug-resistant strains, as did some synthetic non-natural cannabinoids, they say.  The scientists also showed that these substances appear to kill bacteria by different mechanisms than conventional antibiotics, making them more likely to avoid bacterial resistance, the scientists note.  At least two of the substances have no known mood-altering effects, suggesting that they could be developed into marijuana-based drugs without causing a “high.”

Scientists have gained new insight into a mechanism whereby chemotherapy may actually assist the rapid regrowth of tumors after treatment.  The research, published by Cell Press in the September issue of the journal Cancer Cell, also helps to explain why a combination of traditional chemotherapy with drugs that block formation of new blood vessels might impede the devastating tumor recovery that often follows cancer therapy.

“Chemotherapy remains the most commonly employed form of systemic cancer treatment.  However, although partial or complete shrinkage of tumor mass is frequently induced in chemotherapy-responsive tumors, survival benefits of such responses can be compromised by rapid regrowth of the drug-treated tumors,” says senior study author Dr. Robert S. Kerbel from the University of Toronto.

Clinical trials have indicated that drugs that inhibit the growth of blood vessels, called antiangiogenic drugs, can sometimes enhance the effectiveness of traditional chemotherapy.  For example, coadministration of the antiangiogenic drug bevacizumab with the chemotherapeutic agent paclitaxel improves survival benefits for metastatic breast cancer and small cell lung cancer.  In contrast, coadministration of bevacizumab with gemcitabine for treatment of pancreatic cancer does not increase the effectiveness of chemotherapy alone.

“Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors to regrow after therapy,” says author Dr. Yuval Shaked.  Drs.  Kerbel, Shaked, and colleagues had previously shown that treatment with a type of cytotoxic-like agent known as a vascular disrupting agent (VDA) induces rapid mobilization of cells called circulating endothelial progenitors (CEPs) from the bone marrow compartment that helps the tumor to regrow blood vessels and thereby recover from treatment.

The researchers built on this earlier observation by analyzing whether different, conventional chemotherapeutic drugs had variable abilities to impact CEP mobilization and whether antiangiogenic drugs could block chemotherapy-induced CEP responses and hence amplify their effectiveness.  They found that paclitaxel rapidly induced CEP mobilization whereas gemcitabine did not.  They went on to show that pharmacological inhibition of CEP mobilization by combination treatment with an antiangiogenic drug or treatment of mutant mice deficient in CEPs resulted in enhanced antitumor effects mediated by paclitaxel but not gemcitabine.

“Our results provide a new perspective regarding the impact that conventional chemotherapy can have on tumor angiogenesis and hence how combination with antiangiogenic drugs may amplify the antitumor effects of chemotherapy,” explains Dr. Kerbel.  “Further, our findings provide a potential explanation of why not all chemotherapy drugs will necessarily have their efficacy enhanced by the addition of an antiangiogenic agent when the mechanism involves blunting CEP mobilization acutely induced by the chemotherapy drug.”

Researchers from the European Molecular Biology Laboratory (EMBL) discovered a new way to make use of drugs’ unwanted side effects.  They developed a computational method that compares how similar the side effects of different drugs are and predicts how likely the drugs act on the same target molecule.  The study, published in Science this week, hints at new uses of marketed drugs.

Similar drugs often share target proteins, modes of action and unpleasant side effects.  In reverse this means that drugs that evoke similar side effects likely act on the same molecular targets.  A team of EMBL researchers now developed a computational tool that compares side effects to test if they can predict common targets of drugs.

“Such a correlation not only reveals the molecular basis of many side effects, but also bears a powerful therapeutic potential.  It hints at new uses of marketed drugs in the treatment of diseases they were not specifically developed for,” says Peer Bork, Joint Coordinator of EMBL’s Structural and Computational Biology Unit.

The approach would prove particularly useful for chemically dissimilar drugs used in different therapeutic areas that nevertheless have an overlapping, so far unknown protein target profile.  Similar strategies have proven successful in the past.  For example, the drug marketed as Viagra was initially developed to treat angina, but its side effects of prolonged penile erection led to a change in its therapeutic area.

Applying the new method to 746 marketed drugs, the scientists found 261 dissimilar drugs that in addition to their known action also likely bind to other unexpected molecular targets.  20 of these drugs were then tested experimentally and 13 showed binding to the targets that were predicted by side effect similarity.  Testing 9 of these drugs further in cellular assays they all showed activity and thus a desired effect on the cell through their interaction with the newly discovered target proteins.

The results reveal that side effects can help find new, relevant drug-target interactions that might form the basis of new therapies.  The brain enhancer Donepezil, for example, proved to share a target with the anti-depressant Venlafaxine, supporting that Donepezil could be also used to treat depression.

The big advantage of marketed drugs is that they have already been tested and approved for safe use in patients.  This means they can move a lot faster from bench to bedside than newly discovered drugs that often take up to 15 years before they can be applied in patients.

“With some more tests and refinement our method could in future be applied on a bigger scale.  New drugs could routinely be checked in the computer for additional hidden targets and potential use in different therapeutic areas.  This will save a lot of money and would speed up drug development tremendously,” concludes Bork.

The development of resistance to anticancer chemotherapeutic agents remains a large problem. In some cases, such resistance is associated with altered control of a cellular process known as translation, which is central to the generation of proteins. New data, generated by Jerry Pelletier and colleagues, at McGill University, Montreal, have identified a drug that can enhance the sensitivity of mouse cancer cells to standard anticancer chemotherapeutic agents.

In the study, small molecules were screened for their ability to inhibit the initiation of translation by modifying the function of a protein known as eIF4A, which has a central role in translation initiation. A class of natural drugs known as cyclopenta[b]benzofuran flavaglines were found to have the desired effects and one member of this class of compounds was shown to reverse the resistance of cancer cells to anticancer chemotherapeutic agents in a mouse model of lymphoma. The authors therefore suggest that developing approaches to inhibit translation initiation by targeting eIF4A might provide a way to altering drug resistance in cancers exhibiting altered control of translation initiation.

A group of researchers at UT Southwestern Medical Center have developed a simple and inexpensive method to screen small synthetic molecules and pull out a handful that might treat cancer and other diseases less expensively than current methods.

In one screen of more than 300,000 such molecules, called peptoids, the new technique quickly singled out five promising candidates that mimicked an antibody already on the market for treating cancer. One of the compounds blocked the growth of human tumors in a mouse model.

Antibodies are molecules produced by the body to help ward off infection. Natural and manmade antibodies work by latching onto very specific targets such as receptors on the surface of cells.

“Many new drugs being made today are antibodies, but they are extremely expensive to make. Financially, the U.S. health care system is going to have a difficult time accommodating the next 500 drugs being antibodies,” said Dr. Thomas Kodadek, chief of translational research at UT Southwestern and senior author of the study, which appears online and in an upcoming issue of the Journal of the American Chemical Society.

“Our results show that a peptoid can attack a harmful receptor in the body with the same precision as an antibody, but would cost much less to develop,” said Dr. Kodadek.

Peptoids are designed in the laboratory to resemble chains of natural molecules called peptides. Some peptides are used as medications, such as insulin or antibodies used to treat some cancers, but because the stomach digests them, most can’t be taken by mouth and must be injected.

By contrast, peptoids are resistant to the stomach enzymes that degrade natural peptides, so it is possible that they could be swallowed as a pill. Peptoids are much less expensive and easier to manufacture than antibodies, Dr. Kodadek said. They are also much smaller than antibodies, so they might be better at penetrating tumors or other disease sites, he said.

“Our technique is simple and fast, works with existing chemicals and needs no high-tech instrumentation, except for a microscope to detect the fluorescent colors we use to sort the compounds,” said Dr. D. Gomika Udugamasooriya, postdoctoral researcher in internal medicine and lead author of the study.

The new technique also has major advantages over traditional screening techniques that are commonly used to discover biologically active compounds from large collections. These screens, which require extensive automation, generally cost $40,000 or more; the new method can be conducted for less than $1,000.

The researchers screened about 300,000 peptoids to see which ones would interact with VEGFR2, a type of molecule on the surface of human cells. VEGFR2 is essential in creating new blood vessels through interaction with the hormone VEGF, which is normally a helpful process but is harmful to the body when the new blood vessels are nourishing a growing tumor.

A commercially produced antibody is used to treat some cancers by blocking the VEGF-VEGFR2 interaction and thus starving the tumor, but it costs a patient about $20,000 a year, Dr. Kodadek said.

The new screening technology involves hundreds of thousands of peptoids, bound to tiny plastic beads. In the study, the cells with VEGFR2 were labeled to fluoresce red and those lacking VEGFR2 were labeled to fluoresce green. After exposing the beads to the mixture of cells, the beads were examined under a fluorescent microscope. Those bound to red cells — the ones with VEGFR2 — were collected.

This screen, which took a couple of days, isolated five peptoids out of approximately 300,000 screened, showing that the process was an effective way to quickly narrow down a search, Dr. Kodadek said.

The researchers further tested one of the five peptoids that bound most tightly to VEGFR2 and found that it blocked VEGFR2’s action in cultured cells. When they gave it in low doses to mice with implanted human bone- and soft-tissue cancer, the peptoid slowed the growth of the tumors and reduced the density of blood vessels leading to them.

“This new technique of rapidly isolating biologically active peptoids offers a way to hasten the drug-discovery process and may ultimately benefit patients by providing them with new therapies at a fraction of the cost of current drugs,” Dr. Kodadek said.

Other UT Southwestern researchers who participated in the study were general surgery resident Dr. Sean Dineen and Dr. Rolf Brekken, assistant professor of surgery.

The work was supported by the National Heart, Lung and Blood Institute and The Welch Foundation.