Medicine Man

The key to a better drug delivery method for cancer patients may be growing all across the Midwest, South Dakota State University research suggests.

Assistant Professor Omathanu Perumal and his team in SDSU's Department of Pharmaceutical Sciences have been working with submicroscopic particles to deliver medications using the corn protein, zein. Zein is a protein found in distillers grains, a co-product of ethanol production. It is different from other proteins in its unique ability to prevent water absorption. This quality of zein has found applications ranging from food packaging to chewing gums.

Researchers at SDSU are preparing zein nanoparticles for drug delivery. Nanoparticles are tiny particles that can only be seen with an electron microscope. Scientists are entrapping a medication inside the nanoparticles, which Perumal describes as approximately 500 times smaller than the diameter of a strand of human hair. The tiny size of these particles could lend assistance to new cancer therapies, where one challenge is treating the cancer cells without affecting the normal cells around it.

"We can utilize size. In general, the cancerous tissue is physiologically different from the normal tissue," explains Perumal. "One of the things we see in the tumor tissue is that the blood vessels are much 'leakier,' whereas normal blood vessels don't allow particles to be transported through them. "Therefore, if you have really small particles, they will not go into normal tissue, but they can go into the cancerous tissue. This is called passive targeting."

The drug-loaded zein nanoparticles are being delivered by injection in animal experiments, but future tests may explore oral, topical and other delivery methods. When outside objects, including medications, get inside the body, the body's immune system tries to flush them out of the body. In turn, the process affects the length of time that drugs can work in the body before being expelled. These nanoparticles, however, are so tiny that the body doesn't recognize and excrete them.

The technique SDSU researchers are exploring encapsulates drugs within the nanoparticles and delivers them to the affected site. Perumal became interested in using corn zein to form nanoparticles because it satisfied a safe, biodegradable alternative to using a synthetic ingredient and could target specific areas because of its size. The dosage frequency is also reduced because the medication stays longer in the body. Perumal adds that many people, because of religious reasons, don't take in animal proteins, which is one more reason to develop treatment options that use plant-based zein.

The team is currently working with a drug commonly used to treat breast cancer. Experiments examine how much doseage is delivered and its effectiveness compared to traditional methods of delivery. Perumal said results show the treatment meets their expectations.

Perumal's work has been funded by the South Dakota Corn Utilization Council. SDSU has filed a provisional patent and researchers are moving forward with early, pre-clinical studies using mice.

Although his team is now working with human breast cancer cells, Perumal anticipates the expansion of nanoparticle treatment for other conditions. For those with artery blockage around the heart, synthetic stents are inserted to help keep the artery open. Because the stent is a foreign object, the body sometimes tries to combat its existence, causing inflammation. By coating the stent with drug-loaded nanoparticles, Perumal hopes that this could be prevented. As the research enters its third year, Perumal will continue trials with support from the South Dakota Board of Regents.

Assistant professor Omathanu Perumal of SDSU's Department of Pharmaceutical Sciences, shown in the foreground of his laboratory, is researching delivery of cancer medications using a protein from distillers grain. Shown in the background are graduate students Preety Sahdev, right, and Vamsi Venuganti.

http://www.sdstate.edu/

Researchers at the University of Adelaide have developed a novel approach to treating advanced prostate cancer that could be more effective with fewer side effects.

Professor Wayne Tilley and Dr Lisa Butler of the University's Dame Roma Mitchell Cancer Research Laboratories have discovered that by using existing prostate cancer drugs in combination with new drugs at lower doses, they can expect to generate better results for patients than current treatments.

Growth of prostate cancer is initially dependent on hormones called androgens, which traditionally have been suppressed to stop tumour growth. However, despite an initial response, resistance to hormone deprivation often occurs and the tumour starts to grow again, Professor Tilley says.

"Men undergoing hormone deprivation therapy can also experience significant side effects, including reduced libido, impotence, hot flushes, tiredness and sweating, gradual decrease in body hair, reduced bone and muscle strength and cognitive changes," he adds.

Professor Tilley and Dr Butler have successfully killed prostate cancer cells in laboratory studies using low doses of a combination therapy of drugs including bicalutamide (an anti-androgen that opposes the action of androgen on the tumour), and the inhibitors 17AAG and vorinostat.

These new drugs block key cancer survival pathways, but are not particularly effective in killing prostate cancer cells if given alone.

"We can now confirm that a very low level of bicalutamide is capable of inhibiting cancer cell proliferation by more than 10-fold when combined with either vorinostat or 17AAG, making our current treatments much more effective and causing fewer side effects," says Dr Lisa Butler.

All the drugs needed for combination therapy are already approved for use in clinical trials, so the new therapy can be readily tested in patients with advanced prostate cancer.

Professor Chris Sweeney, a world recognised medical oncologist and Director of Clinical Trials at the Royal Adelaide Hospital Cancer Centre, will lead a multidisciplinary team to test the new treatment.

"The ultimate test of this exciting laboratory breakthrough is to see if it improves outcomes and quality of life for men suffering from advanced prostate cancer," he says.

"The strong partnership between medical scientists and clinicians at the University of Adelaide and the Royal Adelaide Hospital means patients can benefit from advances in medical science much faster than in the past."

Professor Tilley is a founding member of the Freemasons Foundation Centre for Men's Health, which is working towards establishing a national prostate cancer research facility in Adelaide.

http://www.adelaide.edu.au/

Family, friends and neighbors remember Lisa Sandler Spaeth as an active mother of two in Potomac, Md., with a lot on the go, juggling her son's baseball games and her daughter's horseback-riding lessons with numerous committee obligations, organizing women's activities at her local synagogue. Add to this Spaeth's thriving home business turned wholesale supplier - making custom hair accessories for children - which she founded with her mother.

But Spaeth was also diagnosed with pulmonary fibrosis, a hard-to-treat disease that progressively damages the lungs and starves the body of oxygen. For two years after her diagnosis, until her death in May 2007, at age 44, Spaeth was beset by fatigue. Her energy levels sank as her lungs deteriorated. Breathing became difficult, and she could no longer attend many of the sporting events, trade fairs and women's groups that filled her life.

It is with people like Spaeth in mind that researchers at Johns Hopkins and elsewhere have found what is likely to be the first evidence linking the extreme fatigue in the lung-scarring disease, which has no known cause, to the poor quality of sleep that results - as much as a 25 percent loss in body-rejuvenating R.E.M. sleep. And they have also gauged the detrimental effects this has on people's daily lives, nearly halving test scores used to assess physical and mental quality of life.

In a report appearing this month in the journal Chest, senior study investigator and pulmonologist Sonye Danoff, M.D., Ph.D., who treated Spaeth, found more than twice the amount of nighttime sleep disturbances and double the number of daytime episodes of drowsiness among 41 men and women with so-called idiopathic pulmonary fibrosis than in people with healthy lungs.

"Physicians should strongly consider monitoring people with this scarring lung disease for sleep disorders as part of their standard care, because poor sleep has a profound effect on their quality of life," says Danoff, an assistant professor at the Johns Hopkins University School of Medicine.

The latest study results back up previous research by Danoff and other sleep experts at Johns Hopkins, which showed that 18 of 22 people with fibrosed lungs had problems breathing while asleep. The majority of them dropped out of R.E.M. sleep during the night, losing 25 percent of total R.E.M. sleep time.

It is during the R.E.M. period that rapid eye movements occur (hence the name), that people dream and that the body recovers from the previous day and builds up energy for the next.

Pulmonary fibrosis makes people highly vulnerable to sleep problems, Danoff says, because they often breathe twice as fast to supply the body with oxygen. And just as breathing and other body functions naturally slow down at the onset of R.E.M. sleep, these people who depend on a higher rate of breathing are constantly being pushed to wake up from a lack of oxygen.

"Essentially," she adds, "the body's internal alarms go off as people enter the most rejuvenating part of sleep. And when people don't get a good night's sleep, they cannot function normally the next day. It's a slippery slope that gets progressively worse over time."

Also in this latest Johns Hopkins study are survey results assessing quality of life and quality of sleep, which showed that people with stiffened lungs and sleep problems have 40 percent lower scores in physical activities compared to the general U.S. population. Rated activities included basic tasks, such as going to the mailbox and walking to the car. Mental and social activities, such as carrying on a conversation with a store clerk or telephoning friends and family, were reduced 48 percent.

Sleep quality was assessed on a scale comprising 36 different sleep measurements, such as the length of time it took to fall asleep and overall time spent sleeping.

Moreover, the team's analysis showed that sleep problems could not be predicted by other demographic factors, such as age, gender, race or weight. Nor were they linked, researchers say, with other lung function and more noticeable disease symptoms, including shortness of breath and cough.

"Because there is so much about pulmonary fibrosis that we cannot yet fix, we need to focus on what we can fix while we wait for research to catch up with treatments that can prevent or reverse the disease," says Danoff.

Current treatments for pulmonary fibrosis are limited to steroids and other immune-system-lowering drugs that help slow down lung tissue deterioration as the thin walls of the air sacs stiffen and lose capacity to freely expand and contract.

More than 200,000 Americans suffer from pulmonary fibrosis, whose cause remains unknown. And the lung disease kills nearly 40,000 each year.

"If we had been able to treat Lisa Spaeth's fatigue from poor quality sleep, then she might have had more time to lead her life as fully as she had been prior to getting sick," says Danoff.

Despite Spaeth's death, her zest for life carries on. Her mother, Froma Sandler, maintains the business. And through the encouragement of family and friends, more than a thousand people have donated to medical research in Spaeth's honor. The largest-ever contributions arrived in May, just prior to the first anniversary of Spaeth's death, when the Maryland-based Robert M. Fisher Memorial Foundation pledged $2 million to Johns Hopkins to help fund Danoff's future studies into pulmonary disease.

"This research funding will lay the groundwork for a more consolidated and comprehensive look at the many factors that may improve and extend the lives of patients with pulmonary fibrosis: from rehabilitation of the lungs to the development and testing of new medications to offset losses in quality of life from fatigue," says Danoff.

Danoff plans to use some of the funding to support studies that monitor patients with pulmonary fibrosis for problems in sleep patterns, especially in deep-sleep R.E.M. patterns, to target for treatment.

Another phase of research, she says, involves testing new devices to support breathing during sleep and to see if these devices improve quality sleep time and abate fatigue.

Funding for this latest study was provided by a fellowship grant from the CHEST Foundation, the philanthropic arm of the American College of Chest Physicians, which also publishes the journal Chest, and by The Johns Hopkins Hospital's General Clinical Research Center.

In addition to Danoff, other Hopkins researchers involved in these studies, conducted solely in Balimore, were Vidya Krishnan, M.D.; Meredith McCormack, M.D., M.H.S.; Stephen Mathai, M.D., M.H.S.; Maureen Horton, M.D.; and Nancy Collop, M.D. Additional assistance was provided by Shikhar Agarwal, M.D., from the Johns Hopkins University's Bloomberg School of Public Health; Brittany Richardson, from the University of Maryland; and Albert Polito, M.D., from Mercy Medical Center.

http://www.hopkinsmedicine.org/ and http://www.chestjournal.org/

On the rocky road of cancer research, Indiana State University scientists have made important discoveries.

In developing vaccines for cancer and infectious diseases, researchers often trick the immune system by mixing "adjuvants" with the vaccines (proteins, killed cancer cell or infectious agents). "Adjuvants" are substances that jump start the immune system by making vaccines more effective.

ISU researchers have found a possible alternative adjuvant for alum to boost the effectiveness of a vaccine. Professor of life sciences, Swapan Ghosh's research team that includes undergraduate and graduate students has developed the adjuvant: phytol and derivatives, which are part of a chlorophyll molecule and vitamin E. Chlorophyll is the pigment in plants that participate in photosynthesis.

Alum is the most widely used adjuvant for humans. However, there is a need for better or alternative adjuvants, and researchers world wide are greatly interested in developing alternative adjuvants, partly because alum has come under attack as to a possible cause of neurological disorders.

"We found that this chlorophyll-derived adjuvant is actually unconventionally useful not only in enhancing cancer vaccines, but also in suppressing adverse autoimmune disorders," Ghosh said. "For example, against lupus, it actually prevents the development or slows down the development of lupus."

As to whether phytol derived adjuvants could be used with or in place of alum, Ghosh said that remains to be tested.

"What we have in mind, actually, is that we can use it by itself because this group of adjuvants also helps prevent Staphylococcus infections and E. coli infections," he said.

At this point, phytol-based adjuvants appear to have little or no toxicity. While on the hunt for effective cancer vaccines, Ghosh and his students' primary goal has been to find a nontoxic booster substance for use in vaccines for lymphoma. The adjuvant research has been published in the Journal of Immune Based Therapies and Vaccines.

"Cancer is not one disease," he said. "The only thing we can say is what we are offering is another weapon to develop treatment for diseases like cancer and infections. Right now, I'm using the blood cell cancers, which are lymphomas and leukemia, but I actually had previously worked on breast cancer and I possibly will handle some other cancers."

In addition to the antigen and adjuvant working together to attract white blood cells, Ghosh and his students seek an adjuvant that is not toxic as well as work is in boosting immunity.

"Vaccine-presenting cells of innate immunity must get attracted first when a vaccine is injected to alarm the immune system," Ghosh said. The immune system then builds up to attack the virus, bacteria or diseases like caner

Ghosh has also collaboration with Richard Kjonaas a professor with ISU's chemistry department and his students, who helped chemically modify phytol, as deemed necessary from Ghosh's research plan for vaccine design.

"We are hoping by developing this new phytol-type adjuvant to find a certain combination in vaccine formulations. This will allow our immune system to fight any abnormal growth like cancer in a specific way," said Youssef Aachoui, of Casablanca, Morocco, who is working on his doctorate in immunology and studying the adjuvant formulation. "What we're doing in our lab is we're trying to study the efficacy of this group of adjuvants in vitro, then in vivo."

Hongtao Li, who was a gynecological doctor in China and now as an ISU doctoral student studying the molecular basis of vaccines, is trying to find a way to evaluate cancer vaccines against lymphoma through the in vitro system.

"This is expected to cut down the use of animals and cut down the cost," she said "We would also know the mechanism about how vaccines are doing their job."

So far, researchers have been able to extend the life of mice with a vaccine.

"We have actually developed a vaccine which can prolong the life of mice three times," Ghosh said. "Our end point - can we get an animal totally tumor free? That's our objective. At this point we have been able only to increase their lifespan from 40 days, to 180 days in at least 25 percent of mice."

In the process of testing and seeking, an Indiana State researcher in Ghosh's Lab also made a discovery.

Nisreen Al-Shaibi a post-doctoral student from Qatar studying antigen-presenting cell biomarkers, helped identify a new protein, DP58 as a marker of the dendritic cell progenitor. Adjuvants are expected first to activate these types of cells and in vitro testing is underway. However the function of DP58 is unknown.

"We need to know the function of this protein in different places," Al-Shaibi said. "We're trying to discover this function."

Its function for now lies in the future, along with a possible cancer vaccine. Ghosh said for now he doesn't see everyone being vaccinated for cancer as people are for mumps, measles and rubella.

"Normal populations will not be vaccinated against cancer because you cannot predict that," he said. "It is only for those who have already had cancer and have gone through primary treatment. But some cancers which are hiding cannot be seen by a surgeon, a microscope or anything else. How do we tackle them? They are hiding, just biding time. Human cancer usually takes about 20 years before they can show up, so if before that, we can handle them, most likely the cure rate will be much higher."

http://www.indstate.edu/

An estimated 2 million children in developing countries die each year from diarrhea, but simple zinc treatment could reduce the risk of such deaths.

Researchers reached this conclusion in a new review of studies involving more than 6,000 children of all ages.

"Our most important finding is that there is strong evidence that zinc supplementation benefits children suffering from diarrhea in developing countries, but only in infants over six months old," said lead investigator Marzia Lazzerini, M.D. "Zinc reduces acute diarrhea duration in terms of mean duration and risk of diarrhea at given days. Zinc also reduces the duration of persistent diarrhea."

Nearly 30 percent of children in the world are zinc deficient, Lazzerini said. She is a pediatrician with the World Health Organization (WHO) Collaborating Centre for Maternal and Child Health in Trieste, Italy.

Zinc deficiency is due primarily to inadequate dietary intake. Relatively expensive foods - such as meat and fish-contain high levels of zinc, the authors say. Although zinc also appears in cheap foods such as nuts, seeds, legumes and whole grain cereal, these foods can reduce absorption of zinc by the body. Zinc cannot be stored in the body.

"The addition of zinc to children in developing countries is rational and appropriate," said William Cochran, M.D., who had no affiliation with the review. "Diarrhea is a contributing factor to the death of millions of children every year throughout the world. It contributes to death in children in the U.S. much less frequently, 100 to 500 [cases] per year," said Cochran, a pediatric gastroenterologist and nutritionist and chair of the Department of Pediatrics at the Geisinger Clinic in Danville, PA.

The review appears in the current issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

The reviewers identified 18 randomized controlled trials enrolling 6,165 children and comparing zinc treatment with placebo. Thirteen trials focused on treatment of acute diarrhea and the other five on treatment of persistent diarrhea.

The reviewers found zinc was effective for diarrhea in children over six months old. By the third day of zinc treatment, children were 31 percent less likely to suffer from acute diarrhea (in two studies) and were 45 percent less likely to do so after five days of treatment (also in two studies), Lazzerini said.

"This benefit withstood extensive subgroup analysis for nutritional status, geographic region, background zinc deficiency, zinc type and study setting," the authors say.

Zinc also reduced diarrhea at by 29 percent after a week of treatment. Diarrhea at day seven can be a signal of persistent diarrhea, which can lead to severe dehydration and death.

Two of the studies included children younger than six months. The results showed no evidence of a therapeutic effect of zinc treatment in these children.

The authors said there were insufficient data to gauge the influence of zinc treatment on death, since the studies under review did not measure mortality. "The trials were not designed to look at hospitalization and mortality, but given these results, it's expected that a policy of zinc supplementation to all children over six months with diarrhea in developing countries could also reduce hospitalization rate and mortality," they concluded.

"Anything that can be done to limit diarrhea and, as a result, not limit the consumption of regular food may be of help in improving the high death rate associated with diarrhea in underdeveloped countries," Cochran said.

Lazzerini M, Ronfani L. Oral zinc for treating diarrhoea in children (Review). Cochrane Database of Systematic Reviews 2008, Issue 3.

The Cochrane Collaboration is an international nonprofit, independent organization that produces and disseminates systematic reviews of health care interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions.

http://www.hbns.org/