Metals could forge new cancer drug

Drugs made using unusual metals could form an effective treatment against colon and ovarian cancer, including cancerous cells that have developed immunity to other drugs, according to research at the University of Warwick and the University of Leeds.

The study, published in the Journal of Medicinal Chemistry, showed that a range of compounds containing the two transition metals Ruthenium and Osmium, which are found in the same part of the periodic table as precious metals like platinum and gold, cause significant cell death in ovarian and colon cancer cells.

The compounds were also effective against ovarian cancer cells which are resistant to the drug Cisplatin, the most successful transition metal drug, which contains the metal platinum.

Dr Patrick McGowan, one of the lead authors of the research from the School of Chemistry at the University of Leeds, explains: "Ruthenium and Osmium compounds are showing very high levels of activity against ovarian cancer, which is a significant step forward in the field of medicinal chemistry.

Sabine H. van Rijt, lead researcher in the laboratory of Professor Peter Sadler in the Department of Chemistry at the University of Warwick, said:

"Most interestingly, cancerous cells that have shown resistance to the most successful transition metal drug, Cisplatin, show a high death rate with these new compounds."

Professor Sadler, at the University of Warwick, commented that he is "excited by the novel design features in these compounds which might enable activity to be switched on and off".

Cisplatin was discovered in the 1970s and is one of the most effective cancer drugs on the market, with a 95% cure rate against testicular cancer. Since the success of Cisplatin, chemists all over the world have been trying to discover whether other transition metal compounds can be used to treat cancer.

In this type of anti cancer drug transition metal atoms bind to DNA molecules which trigger apoptosis, or programmed cell death, in the cancerous cells.

The study is a collaboration between the universities of Warwick and Leeds and was funded by the Engineering and Physical Sciences Research Council (EPSRC).

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New research strategy for understanding drug resistance in leukemia

UCSF researchers have developed a new approach to identify specific genes that influence how cancer cells respond to drugs and how they become resistant. This strategy, which involves producing diverse genetic mutations that result in leukemia and associating specific mutations with treatment outcomes, will enable researchers to better understand how drug resistance occurs in leukemia and other cancers, and has important long-term implications for the development of more effective therapies.

Findings are reported in the Advance Online Publication of the journal “Nature” and are available at http://www.nature.com/nature/journal/vaop/ncurrent/index.html.

“In trying to understand why certain cancers respond to drugs while certain other cancers fail to respond, we found that a single gene can be the culprit for drug resistance,” said Kevin Shannon, MD, senior author of the paper and a pediatric cancer specialist at UCSF Children’s Hospital. “The subtlety of what makes a cancer cell become resistant to a drug is truly remarkable.”

“When treating patients for cancer, clinical specialists usually only have one or two chances to choose the right drug before it is too late. This makes it incredibly important to understand drug resistance so that we can prioritize therapeutic options,” said Jennifer Lauchle, MD, the study’s lead author and a pediatric blood and cancer specialist at UCSF Children’s Hospital.

In the initial stages of the study, the researchers used a strain of mice that developed acute myelogenous leukemia, or AML, to assess the effectiveness of an experimental cancer drug called a MEK inhibitor. AML is an aggressive cancer that affects both children and adults and causes abnormal white blood cells to grow rapidly and accumulate in the bone marrow, thereby interfering with the production of normal blood cells.

The researchers created the mouse model of AML through two key steps. First they utilized a strain of mice that had a single gene mutation closely resembling the mutation found in leukemia and some other cancers. Then they introduced an infectious particle called a retrovirus, which produces additional mutations that work together and result in AML. The retrovirus also “tags” these new genetic mutations, which allows researchers to identify them later on. These steps resulted in a model of AML that, like human AML and other advanced cancers, has several genetic mutations that interact with one another.

To assess the effectiveness of the MEK inhibitor, the researchers compared a group of mice with AML that was treated with the drug to a group that was left untreated and found that the drug increased survival time threefold. However, all of the leukemia cells that initially responded to the drug later relapsed, which is similar to what happens in many human patients.

“This shows that even if you make what seems to be a really good drug, resistance is a major problem that must be overcome,” said Shannon, who is also a leader of the hematopoietic malignancies research program at UCSF’s Helen Diller Family Comprehensive Cancer Center.

In the next phase of the study, the research team set out to uncover the genes that triggered drug resistance by comparing cells from the original drug responsive AML to those of the relapsed AML. Because AML in the mouse model had been created with a retrovirus, the new mutations that caused the leukemia to relapse could be pinpointed through forward genetic analyses. These analyses identified two new single gene mutations that rendered the MEK inhibitor ineffective and brought about the relapsed AML.

According to the researchers, this same method can be used to study other types of cancer in order to identify additional genes responsible for drug resistance. “The hope is that this new strategy will enable us to identify more effective therapies and to find ways to anticipate and overcome drug resistance,” Shannon added.

Additional co-authors from UCSF include Doris Kim, Doan Le, MD, Michael Crone, Kimberly Krisman, Kegan Warner, Jeannette Bonifas, Qing Li, MD, Kristen Coakley, Ernesto Diaz-Flores, PhD, Matthew Gorman, MD, Mary Tran, Scott Kogan, MD, and Jeroen Roose, PhD. Co-authors from other institutions are Keiko Akagi, PhD, and Linda Wolff, PhD, of the National Cancer Institute; Sally Przybranowski, MS, and Judith Sebolt-Leopold, PhD, of Pfizer Global Research and Development; Neal Copeland, PhD, and Nancy Jenkins, PhD, of the Institute of Molecular and Cell Biology; and Luis Parada, PhD, of the University of Texas Southwestern.

The research was supported by grants from the National Institutes of Health, the Leukemia and Lymphoma Society, the US Army Neurofibromatosis Research Program, the Ronald McDonald House Charities of Southern California/Couples Against Leukemia, the Jeffrey and Karen Peterson Family Foundation, and the Frank A. Campini Foundation.

One of the nation’s top children’s hospitals, UCSF Children’s Hospital creates an environment where children and their families find compassionate care at the healing edge of scientific discovery, with more than 150 experts in 50 medical specialties serving patients throughout Northern California and beyond. The hospital admits about 5,000 children each year, including 2,000 babies born in the hospital.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Source : news.ucsf.edu

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Biovail stumbles on Phase III testing for Parkinson's drug

The risks of Biovail Corp.'s expansion into drugs for the central nervous system became apparent yesterday when a trial of a new treatment for Parkinson's disease failed.

The Toronto-based pharmaceutical giant, and its U.S. partner, Acadia Pharmaceuticals Inc., said a Phase III trial of the drug pimavanserin, which is supposed to treat hallucinations and delusions that often come with Parkinson's disease, did not meet its goals. In the trial with almost 300 patients, those treated with a placebo fared better than those getting one of the two trial dosages.

This is a disappointment, given Biovail's new focus on developing and marketing drugs for disorders of the central nervous system (CNS), but is not a significant setback, said chief executive officer Bill Wells.

"This sort of thing is to be expected in the drug development business," he said in an interview. "Phase III failures are quite normal."

Biovail's CNS strategy is unchanged, he said. "This game is all about shots on goal, which is why we wanted to build a portfolio of opportunities, understanding that the majority of those would fail, but the one or two which are successful will pay for all the rest."

Acadia and Biovail said they will examine the trial data in more detail before deciding whether to abandon the drug altogether. Pimavanserin also has potential to treat other diseases, such as Alzheimer's, and there is "a reasonable possibility we might have some other directions to go," Mr. Wells said.

For Acadia, a San Diego-based company that has only a small number of drugs in its pipeline, the failure is much more serious than for Biovail, which has a large portfolio of products. The response from investors underlined this, as Acadia shares plunged 66 per cent on the Nasdaq Stock Market yesterday, while Biovail's fell just 3 per cent on the Toronto Stock Exchange.

Biovail was not expecting any revenue from pimavanserin until at least 2012, so there is no short-term impact on the company, said Claude Camiré, an analyst at Paradigm Capital Inc. in Toronto.

While the new drug would have been helpful if it had been successful, the setback will push Biovail to make other acquisitions and diversify its risk, he said. Biovail is still one of the fastest-growing drug companies in the world, Mr. Camiré said, and he is maintaining his "buy" recommendation on the stock.

Biovail signed its deal with Acadia in May, paying an upfront fee of $30-million (U.S.) for the right to develop, manufacture and commercialize pimavanserin in Canada and the United States. Biovail agreed to make further payments in the hundreds of millions, if the drug were to meet specific milestones leading to commercialization. So far, no more payments have been made.

Acadia's CEO Uli Hacksell told analysts on a conference call that his company will go ahead with another Phase III trial of pimavanserin for Parkinson's, set to be complete in about a year. If the drug completely fails for Parkinson's, it might be useful for other diseases, Mr. Hacksell said.

"While we are obviously disappointed in the data we announced today, we still believe in the potential of pimavanserin as a product candidate, based on our clinical experience to date with this compound and its attractive safety profile," he said. "We haven't given up on pimavanserin."
Source : www.theglobeandmail.com

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New Route To Potential Breast Cancer Cure Discovered

UK scientists have discovered a new route to a potential cure for breast cancer, one that focuses on how the cancer manipulates genetic pathways to spread through the body, rather than on how tumors develop in the first place. They are already working on a new drug to switch off the cancer's effect on the pathways and say it could be ready in a couple of years, but experts suggest this could be rather optimistic.

The landmark study was the work Dr Justin Stebbing of Imperial College London (ICL) and other colleagues from ICL and also from the Howard Hughes Medical Institute, Cold Spring Harbor Laboratory in New York, USA. They have written a paper on it in the 24 August online before print issue of the Proceedings of the National Academy of Sciences, PNAS.

Stebbing, who is senior lecturer and consultant medical oncologist at ICL was reported by the Daily Express as telling the media that the new discovery was a "step on the way" to a potential cure for breast cancer.

"It helps us understand the way breast cancer cells grow and divide and if we understand this then we understand how to stop it," said Stebbing.

Breast cancer is the most common cancer of women in the western world, in Britain alone it kills 12,000 women a year.

In most cases the cancer depends on estrogen to fuel tumor growth, and current treatments focus on inhibiting the activity of the estrogen receptor. These treatments, for example tamoxifen, have been very successful at reducing deaths from breast cancer.

"The estrogen receptor is incredibly important in breast cancer," said Stebbing.

"Most of the treatments around treating breast cancer are blocking it or inhibiting the oestrogen but despite that about half of all women relapse," he added.

Many patients relapse because they eventually become resistant to hormone therapies.

Cancer is essentially a process where cell growth gets out of control. One of the ways that healthy cells stop growth getting out of control is via microRNA molecules that use genetic pathways to control various cellular processes in the body, such as making proteins.

As Stebbing explained:

"The way to cure breast cancer or any cancer is by fundamental biological understanding of what turns cells on and off, stopping the way tumours grow."

Stebbing and colleagues' breakthrough has been to discover how cancer cells switch off the microRNA molecules that control cell division to unleash the growth and proliferation of malignant cells.

"We can use these microRNAs as a new treatment and make them do what current drugs don't do," said Stebbing.

He said they had found a new microRNA pathway that the estrogen receptor activates. In normal cells estrogen encourages the production of microRNAs, but then as more of them are produced, they switch off estrogen activity, and this keeps cell division under control. Stebbing described this as a "perfect circle".

"But in breast cancer cells, production of the molecules is turned off," said Stebbing, and this is how the control over cell division is then lost and the malignant cells proliferate.

So their aim is to produce a drug that restores the "perfect circle" by stopping the deactivation of the microRNAs.

"If we know how to stop it then we can cure it. This only applies in oestrogen positive breast cancer but this could save millions of lives," said Stebbing.

Experts welcomed the discovery but had reservations about a drug being available soon.

According to the Daily Express, Dr Laura Bell, of Cancer Research UK, said it was far too early to say whether the discovery will "translate into clinical benefits for people with cancer". She said there was still a lot of work to be done.

Agreeing, Dr Alexis Willett, of Breakthrough Breast Cancer reportedly said, "this research is still at a very early stage".

Source : www.medicalnewstoday.com

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New chemical synthesis could streamline drug design

A team of MIT chemists has devised a new way to add fluorine to a variety of compounds used in many drugs and agricultural chemicals, an advance that could offer more flexibility and potential cost-savings in designing new drugs.

Drug developers commonly add fluorine atoms to drugs, such as the cholesterol-lowering rosuvastatin, to keep the body from breaking them down too quickly. Many of these drugs contain aromatic rings — a type of six-carbon ring — and attaching a fluorine atom to the rings can be a difficult, expensive process.

"It's hard to add fluorine at a late stage, once you have a complete molecule already put together, because traditional methods can be quite harsh with respect to temperature or other factors," says Stephen L. Buchwald, the Camille Dreyfus Professor of Chemistry at MIT.

In their new technique, Buchwald and his colleagues used a palladium catalyst to attach a fluorine atom to aromatic compounds. The technique could be used in the design and testing of new drugs, or to create new imaging agents for positron emission tomography (PET) scanning.

Donald Watson, a former postdoctoral associate in Buchwald's lab, now an assistant professor of chemistry at the University of Delaware, is lead author of a paper describing the new synthesis in the Aug. 13 early online edition of Science.

During the new process, the palladium catalyst removes a group of atoms called a triflate attached to the aromatic compound, then replaces it with a fluorine atom taken from a simple salt, such as cesium fluoride. This marks the first time chemists have replaced a triflate attached to an aromatic ring with a fluorine atom in one catalytic reaction.

"Many people believed it would not be possible to do this," says Buchwald.

"While the method is probably not currently efficient enough to be used in manufacturing, we are working to speed up the reaction, increase its efficiency and make it more environmentally and user-friendly," says Buchwald. "We ultimately hope to make it general enough to be useful for manufacturing."

Source : www.eurekalert.org

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Scientists Test New Way to Get Drugs to Cancer Cells

Nanoparticles that can carry cancer-killing radioisotopes directly to tumors show promise, U.S. researchers report.

The nanoparticles are made with liposomes, small chemical spheres made of fatty molecules that can be designed to carry a number of drugs and chemicals, and can be manipulated to control how long they remain in the bloodstream.

Johns Hopkins University researchers attached cancer-specific antibodies to liposomes to create immunoliposomes that travel through the bloodstream and seek out tumors. When they come in contact with tumors, the immunoliposomes deliver their payload into cancer cells.

"It's a promising approach to solving the problem of how to deliver more of a therapeutic to cancer cells," research leader and radiology professor George Sgouros said in a news release from the American Association of Physicists in Medicine.

The research was to be presented July 28 at the association's annual meeting, in Anaheim, Calif.

In a study on mice, Sgouros and his colleagues loaded the immunoliposomes with alpha-particle emitters, which are powerful radioisotopes that can kill cancer cells without damaging nearby healthy cells. The treatment substantially extended the survival of mice that had aggressive metastatic breast cancer.

"This treatment is much less toxic than chemotherapy because it is targeted to tumor cells rather than to all rapidly dividing cells," Sgouros said. "Nanoparticles designed to deliver these powerful isotopes have a great potential in cancer therapy, particularly for metastatic disease."

Source : www.drugs.com

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New Cancer Drug To Be Tested In Wichita

Increasing access to Phase I clinical trials throughout the state is becoming a reality today as officials from The University of Kansas Cancer Center and the Cancer Center of Kansas announced opening Nanotax, a Phase I clinical trial in Wichita.

This is the first Phase I clinical trial discovered, developed and delivered by The University of Kansas Cancer Center, which is a critical component of achieving National Cancer Institute (NCI) designation.

Often the side effects of chemotherapy are as difficult for patients to cope with as the cancer itself. Nanotax, a reformulation of the commonly used chemotherapy drug Paclitaxel, enables the drug to be mixed with water, which significantly reduces its negative side effects.

Nanotax initially opened at The University of Kansas Cancer Center in June 2008. The trial will enroll approximately 21 patients total with advanced peritoneal cancers.

“Our mission is to ensure everyone across the state has access to cutting-edge clinical trials no matter where they live,” said Roy A. Jensen, MD, director of The University of Kansas Cancer Center. “Opening the Phase I clinical trial Nanotax in Wichita moves us closer to fulfilling this mission by giving patients more options close to home.”

Eligible patients can participate in the trial at the Cancer Center of Kansas, under the direction of Shaker Dakhil, MD, FACP, and Thomas Schulz, MD. Drs. Dakhil and Schulz are nationally known oncologists who currently conduct 116 Phase II and Phase III clinical trials.

“The Cancer Center of Kansas has provided patients access to cutting-edge clinical trials for many years,” said Shaker Dakhil, MD, president of the Cancer Center of Kansas. “This Phase I clinical trial will complement the already extraordinary program we have in place and will allow us to offer more options to our patients.”

The trial also complements the Community Clinical Oncology Program (CCOP) grant the Cancer Center of Kansas holds from the National Cancer Institute (NCI), which provides access to Phase II and Phase III clinical trials.

Funding to support the infrastructure needed to conduct a Phase I clinical trial was provided by the Kansas Bioscience Authority (KBA) earlier this year through the Collaborative Cancer Research Initiative program.

The technology that led to the discovery of Nanotax was developed by University of Kansas researchers and was licensed to CritiTech, Inc., a Lawrence-based biotechnology firm, which patented, developed, produced and filed the investigational new drug application with the Food and Drug Administration (FDA). Collaborating with CritiTech and Beckloff and Associates, researchers at The University of Kansas Cancer Center developed the clinical trial.

Demonstrating the ability to translate discoveries made in the lab into new drugs and enrolling patients onto the clinical trial of the new drug helps The University of Kansas Cancer Center meet key criteria needed to apply for NCI designation. Showing the Cancer Center’s ability to conduct translational research while extending the benefits of its research beyond its center is a hallmark of an NCI-designated center.

Source : www.kake.com

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The Truth About Generics from A Vet School

Making your way down the drug aisle it's often hard to find what you're looking for with hundreds of brightly-colored boxes distracting your focus. To complicate matters further, nearly every name brand medication has at least one or two generic forms packaged in a similar fashion. Staring at the price difference amongst the products, it begs the question, is that expensive name brand drug really the same as the cheaper generic?

"Yes," says Dr. Levent Dirikolu, an assistant professor at the University of Illinois College of Veterinary Medicine who teaches a pharmacology course to veterinary students, "the pharmacologic affects of generics are exactly the same as the name brand drug." For the Food and Drug Administration (FDA) to approve the generic form of a drug, the company producing it must prove their compound is basically a copy of the original.

Although your animal companion might not be strolling the drug store for cough medicine anytime soon, generic drugs affect veterinary patients just like they do their human counterparts. According to the Congressional Budget Office, generic medications save consumers $8-10 billion each year. Since the majority of animal owners don't have health insurance for their pet, saving money on medications is important.

Some speculate that the reason generics are cheaper is because the product is made from less superior ingredients. Dr. Dirikolu notes that, "the pricing of generics has nothing to do with quality." Instead, the lower cost to the consumer has to do with the fact that generic drug companies do not have to carry out expensive research trials for FDA approval.

For example, it would not be uncommon for a pharmaceutical company to spend close to a billion dollars to perform the necessary research ensuring the safety and efficacy of their product. In return for their expenditures, the FDA grants the company the right to produce and market their drug exclusively, usually for around 11 years, in order to recoup their losses. However, once the patent runs out, it is permissible to produce the drug in a generic form.

Although Dr. Dirikolu notes that, "generics are as safe and effective as the brand name drug," there are a few differences between the two. For one, a generic cannot look exactly the same as the brand name drug. The two must look distinctly different, therefore the color or shape will be changed. In addition, though the active ingredient remains in the same dosage, the chemicals used to hold the drug together (inactive ingredients) may be different.

Because very few veterinary drugs ever make it to generic form when compared to human pharmaceuticals, a new trade organization called the Generic Animal Drug Alliance (GADA) is working to aid pet owners save money by helping generic animal drug companies navigate through federal regulations and congress. According to statistics on their website, 77 percent of dogs and 53 percent of cats received medication in 2007.

If you have questions about whether your pet can switch to a generic medication, please contact your local veterinarian. To search for generic equivalents of a name brand drug, you can visit the FDA's Orange Book, which lists approved equivalents, at:
http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm.

Source : yournewpets.com

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New Alzheimer's Gene Is Pinpointed

New research has pinpointed a gene that could improve predictions of who will develop Alzheimer's and at what age.

Allen Roses, director of Duke University's Deane Drug Discovery Institute, said that if other researchers get the same findings, it could mean a drastic improvement in the accuracy of predictions about the disease as well as the approximate age within a five-to-seven-year window when individuals might begin noticing symptoms. And if drugs to slow the course of Alzheimer's become available, the gene could help identify who should begin taking those drugs earlier.


In 1993, Dr. Roses reported that people who have a variant of the ApoE gene have an unusually high risk of developing Alzheimer's. Despite facing initial skepticism, his findings have since been replicated by a number of independent scientists. Testing for the gene variant, called ApoE4, has become accepted as a way of identifying individuals at high genetic risk for Alzheimer's.

But investigators haven't found drugs that slow the disease in these ApoE4-positive individuals; they have only been able to identify their risk of getting the disease. Also, the ApoE4 findings don't explain why many people with the most common version of the gene, ApoE3, also get the disease.

In research presented Sunday at the International Conference on Alzheimer's Disease in Vienna, Dr. Roses and his team looked at the area of DNA surrounding the ApoE gene. They found that a gene linked to ApoE called TOMM40 had mutations that involved a small number of extra copies of a particular building block of DNA in some individuals and a large number of extra copies in others.

Individuals with the large number of extra copies -- known as the "long repeat" version of TOMM40 -- coupled with ApoE3 develop Alzheimer's an average of seven years earlier -- about age 70 -- compared with ApoE3 individuals with a "short repeat" version of TOMM40.

"What you need is the information on the repeat in order to make sense of what type [of ApoE3] you have," said Dr. Roses, who started a company, Zinfandel Pharmaceuticals, to help fund the research.

The researchers used several pools of people with and without Alzheimer's to identify and confirm the genetic findings, including a small group who agreed to have their brain autopsied upon their deaths.

Some scientists urged caution about the new findings. "Before I get too excited about it, I'd like to see it confirmed in more patient populations," said William Thies, president of the Alzheimer's Association, which is sponsoring the conference. With any single study, it is important to make sure the results aren't a result of "statistical anomaly," Dr. Thies said.

The TOMM40 gene is related to how easily molecules can get into and out of the surface of the mitochondria, the energy center of cells. Some researchers propose that this permeability is part of Alzheimer's disease, according to Dr. Thies. One experimental drug called Dimebon, which is being studied by Medivation Inc. and its partner Pfizer Inc., may be a therapy that acts through that mechanism, Dr. Thies said.

Zaven Khachaturian -- the former director of Alzheimer's research at the National Institutes of Health who currently runs Khachaturian Radebaugh & Associates Inc., an international consulting group on Alzheimer's and aging -- called the findings "quite significant."

"I do get excited about the possibility of having a good genetic marker that's going to tell us with greater precision who's going to get it and within a time window," Dr. Khachaturian said. "I also have skepticism that we need to validate with larger numbers before we go public."

Source : online.wsj.com

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