Nymox Pharma has developed a new drug to more effectively treat prostate enlargement, a common and troublesome affliction of men in mid to later age

Scientists at Sunnybrook Research Institute (SRI) are developing and commercializing a promising novel therapy for the treatment of prostate cancer that may offer patients a faster and more precise treatment than existing clinical alternatives, with fewer side effects.

The new treatment–magnetic resonance imaging (MRI)-guided transurethral ultrasound–uses heat from focused ultrasound to treat cancer in the prostate gland precisely while sparing the delicate noncancerous tissues around the prostate essential for healthy urinary, bowel and sexual function.

Sunnybrook researchers Dr. Michael Bronskill and Dr. Rajiv Chopra have licensed their innovation and formed Profound Medical Inc., which will develop the technology for clinical use.

Unlike surgical removal of the prostate, the treatment is minimally invasive and could be performed without a lengthy hospital stay. In preclinical studies, treatment takes less than 30 minutes. The therapy, on which clinicians at Sunnybrook will conduct preliminary testing in preparation for a clinical trial, could help limit the number of men living with the common, debilitating and often permanent side effects of surgery and radiation treatments currently used. More of these invasive therapies are being performed now because improved awareness among younger men has converged with better clinical detection tools.

Profound’s clinical development is targeted at treatment that reduces the high level of incontinence and impotence associated with current, invasive treatments. The therapy involves two different and naturally incompatible technologies, ultrasound and MRI, which Bronskill and Chopra spent 10 years making compatible. “You have to make an ultrasound heating applicator work inside a magnetic resonance imager, without the two technologies interfering with each other,” says Bronskill, who is a professor at the University of Toronto. “The prostate cancer site is a natural for this technology because it’s surrounded by structures you want to spare.” Dr. Laurence Klotz, chief of urology at Sunnybrook Health Sciences Centre, and a professor at the University of Toronto, says that a noninvasive therapy for early, localized prostate cancer could improve the quality of life of hundreds of thousands of men. “The key to effective noninvasive treatment is accurate imaging of the target organ and of the effects of the treatment on tissue. In that respect, MR-guided ultrasound has many potential advantages over transrectal ultrasound-guided focused ultrasound, now approved for use in Canada,” says Klotz.

The scientists’ creation of this clinically viable product was done in a setting committed to commercialization. “At SRI, we are dedicated not only to developing new and better therapies and technologies, but also to getting those discoveries to our patients,” says Dr. Michael Julius, vice-president of research at Sunnybrook. Profound Medical Inc. is the third imaging-technology company to be spun out of research at SRI in recent years. The other two are VisualSonics Inc. and Sentinelle Medical Inc.

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Using a combination of a targeted cancer-fighting agent called DFMO and a low dose of an anti-inflammatory drug, UC Irvine researchers have reduced the risk of reoccurring colorectal polyps, an early sign of colon cancer, by as much as 95 percent with fewer toxic side effects.

The study marks a breakthrough in the effort to combat colon cancer, the third leading cause of cancer in men and fourth in women, according to Dr. Frank L. Meyskens Jr., the Daniel G. Aldrich Chair at UC Irvine and director of its Chao Family Comprehensive Cancer Center.

“There is a great hope that we will be able to prevent colon cancer effectively using this method,” said Meyskens, who led the clinical trial effort to test this drug combination. He presented his findings at the American Association for Cancer Research annual meeting in San Diego.

In earlier studies, Meyskens had established a safe and well-tolerated dose of DFMO (difluoromethylornithine) that was 1/50 of what would typically be used to treat advanced cancers. By combining this reduced dose of DFMO with a non-steroidal, anti-inflammatory drug called sulindac, researchers believed they could improve treatment and decrease the reoccurrence of potentially cancerous colon polyps with reduced toxic side effects.

DFMO is the basis of the drug eflornithine, which was initially developed as a cancer medication and is no longer manufactured commercially for that purpose. Sulindac is sold commercially as Clinoril and is used to treat arthritis and other inflammatory conditions.

The researchers enrolled 375 patients who had a history of at least one colorectal polyp, or adenoma, within the previous five years. Patients were randomly assigned to either a combination of 500 mg of daily DFMO and 150 mg of sulindac or placebos. Patients were followed for three years, and adenoma recurrence was measured by colonoscopy. Among the results:

* Overall risk for recurrent adenoma: 41.1 percent in placebo group to 12.3 percent in treated patients, a 79 percent reduction

* Risk for recurrent advanced adenomas: 8.5 percent in placebo group to 0.7 in treated patients, a 92 percent reduction

* Risk for adenomas larger than one centimeter: 7 percent in the placebo group to 0.7 percent in the treatment group, a 90 percent reduction.

* Rate of repeating adenoma among patients who had previously had more than one adenoma: 13.2 percent in the placebo group to with 0.7 percent in the treatment group, a 95 percent reduction.

The rate of reduction was so pronounced that the trial’s independent data and safety monitoring board stopped the trial early.

An analysis of side effects and toxicity found no difference between the treatment and placebo groups. There also was no difference in side effects requiring an overnight hospitalization, gastrointestinal side effects or cardiovascular side effects between the two groups.

“What we have shown here is that there is value in testing these agents at lower doses and in combination to determine if we can achieve the same effect without the damaging side effects,” Meyskens said.

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Hormones produced by the heart eliminated human pancreatic cancer in more than three-quarters of the mice treated with the hormones and eliminated human breast cancer in two-thirds of the mice, according to researcher David Vesely, a doctor at the James A. Haley Veterans Hospital in Tampa and a professor at the University of South Florida (USF).

Credit: iStockphoto

The treatment has not yet been tried in humans, but a private biotechnology company is raising money in the hope of beginning human trials. Vesely is the hospital’s chief of endocrinology, diabetes and metabolism and is also professor of medicine, molecular pharmacology and physiology at USF.

The discovery of cardiac hormones

For more than 350 years, scientists and physicians thought the heart was a pump, delivering blood and oxygen to the body. But that view changed dramatically in 1981 when Adolfo deBold discovered that the heart produces atrial natriuretic factor (ANF), so-named because it is produced in the atrium of the heart and stimulates the production of urine and the excretion of sodium.

Vesely later discovered three more hormones that are produced from the same gene as ANF. He called them:

* Long acting natriuretic peptide, which also stimulates urine production and sodium excretion.
* Vessel dilator which opens the blood vessels and lowers blood pressure
* Kaliuretic peptide which increases potassium excretion

The hormones, called peptide hormones because they are composed of amino acids, help regulate blood volume and blood pressure. Most hormones, including such well-known hormones as insulin, are peptide hormones.

Started with congestive heart failure research

Vesely began his research on cardiac hormones by looking at the role they can play in diagnosing and treating congestive heart failure. Following his wife’s death from breast cancer in 2002 — and as it became clear that the hormones controlled cell growth — he decided to place the hormones into cancer cell cultures.

Using colon, ovarian, breast, prostate and pancreatic cancer cells, among others, Vesely found that the hormones kill up to 97% of all cancers in cell cultures within 24 hours. He then turned to trials with mice, injecting some with pancreatic cancer cells and others with breast cancer cells. Once the mice developed tumors, he treated them with the hormones.

At the end of one month, the treatment had eliminated cancer in 80% of the mice injected with human pancreatic cancer and in 66% of the mice injected with breast cancer. The results with pancreatic cancer were particularly exciting because it is a fast-moving cancer with poor prognosis.

No side effects in mice

The pancreatic cancers that were not cured were reduced to less than 10% of their original size. Treatment with vessel dilator gave the best results: reducing the tumor to 2% of its largest size. None of the mice died of cancer – all died of old age – and none suffered any side effects.

None of the mice received any other course of treatment such as surgery, chemotherapy or radiation and they did not suffer any side effects. After the mice died at the end of a normal life span, the researchers found that the cancer had not spread. If the hormones act the same way in humans, cancer could become a chronic condition treatable with these hormones, Vesely said.

A private biotechnology company is raising money to begin human trials, Vesely said. The Haley hospital and University of South Florida hold the patents on the discoveries.

Vesely will present his research at a symposium April 9 at the Experimental Biology 2008 conference in San Diego. The American Federation for Medical Research sponsors the session, which takes place during the annual meeting of The American Physiological Society.

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Researchers at the Duke School of Medicine apparently have solved the riddle of why cancer cells like sugar so much, and it may be a mechanism that could lead to better cancer treatments.

In normal cells, growth factors regulate metabolism and cell survival. Removing these factors leads to loss of glucose uptake and metabolism and cell death. Cancer cells, however, maintain glucose metabolism and resist cell death, even when deprived of growth factors.

To study how Akt might affect these processes, Coloff and colleagues introduced a cancer-causing form of Akt called myrAkt, into cells that depend on growth factor to survive. The mutant form of Akt allowed cells to maintain glucose usage and survive even when no growth factors were present, allowing them to bypass a normal safeguard used by cells to prevent cancer development.

The death of normal cells after growth factors are removed is partly accomplished by two proteins called Mcl-1 and Puma. But the cancer-causing version of Akt prevents these two proteins from accomplishing their tasks, allowing the cell to survive when it shouldn’t.

Once glucose was withdrawn from the environment, however, Akt was no longer able to maintain regulation of the key targeted proteins Mcl-1 and Puma, and the cells died.

“Akt’s dependence on glucose to provide an anti-cell-death signal could be a sign of metabolic addiction to glucose in cancer cells, and could give us a new avenue for a metabolic treatment of cancer,” said Dr. Rathmell.

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A revolutionary cancer treatment using microscopic magnets to enable ‘armed’ human cells to target tumours has been developed by researchers funded by the Biotechnology and Biological Sciences Research Council (BBSRC). Research published online today in the journal, Gene Therapy, shows that inserting these nanomagnets into cells carrying genes to fight tumours, results in many more cells successfully reaching and invading malignant tumours.
Using human cells as delivery vehicles for anti-cancer gene therapy has long been an attractive approach for treating tumours, but these cells usually reach tumours in insufficient numbers to effectively attack them. Now, a new ‘magnetic targeting’ method has been developed to overcome this problem by Professor Claire Lewis at the University of Sheffield, Professor Jon Dobson at the University of Keele, and Professor Helen Byrne and Dr. Giles Richardson at the University of Nottingham.

The technique involves inserting nanomagnets into monocytes – a type of white blood cell used to carry gene therapy – and injecting the cells into the bloodstream. The researchers then placed a small magnet over the tumour to create a magnetic field and found that this attracted many more monocytes into the tumour.

The head of the laboratory in which the work was done, Professor Lewis, explains: “The use of nanoparticles to enhance the uptake of therapeutically armed cells by tumours could herald a new era in gene therapy – one in which delivery of the gene therapy vector to the diseased site is much more effective. This new technique could also be used to help deliver therapeutic genes in other diseases like arthritic joints or ischemic heart tissue.”

Professor Jon Dobson from the University of Keele, said: “Though the concept of magnetic targeting for drug and gene delivery has been around for decades, major technical hurdles have prevented its translation into a clinical therapy. By harnessing and enhancing the monocytes’ innate targeting abilities, this technique offers great potential to overcome some of these barriers and bring the technology closer to the clinic.”

Professor Nigel Brown, BBSRC Director of Science and Technology, said: “This exciting work could have huge implications in healthcare. Fundamental bioscience research may sometimes seem to have little relevance to everyday life, but understanding the basic workings of the human body and harnessing nanoscale technology has resulted in a process of great potential in tumour therapy.”

The team are now looking at how effective magnetic targeting is at delivering a variety of different cancer-fighting genes, including ones which could stop the spread of tumours to other parts of the body.

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Heart surgeons at Washington University School of Medicine in St. Louis report that by adding a simple 10-20 second step to an operative procedure they achieved a significant improvement in the outcome for the surgical treatment of atrial fibrillation (AF).
Reporting in the April issue of the Journal of Thoracic and Cardiovascular Surgery, the surgeons describe an enhancement to the Cox-Maze procedure, a surgical procedure that redirects wayward electrical impulses causing AF by creating precisely placed scars, or ablations, in the heart muscle. The Cox-Maze procedure is highly effective, offering the best long-term cure rate for persistent atrial fibrillation.

The surgeons added one ablation to the series of ablations typically made during the Cox-Maze procedure and that short step improved how well patients did after surgery. As a result, they recommend using this extra ablation in all patients undergoing the procedure.

“The single additional ablation creates what we call a box lesion,” explains Ralph J. Damiano Jr., M.D., the John Shoenberg Professor of Surgery at the School of Medicine. “The box lesion surrounds and electrically isolates the pulmonary veins and the posterior left atrial wall from the rest of the left atrium. Our study shows excellent success when using the box lesion, and we recommend it for any patient with long-standing atrial fibrillation.”

AF is the most common irregular heart rhythm and affects more than 2 million people in the United States. During atrial fibrillation, the upper chambers (atria) of the heart beat rapidly and quiver instead of contracting, drastically reducing the amount of blood they pump. AF can cause fatigue, shortness of breath, exercise intolerance, heart palpitations and stroke.

The area of the heart near the pulmonary veins is a common source of the irregular electrical impulses that can cause AF. Without the box lesion, in some patients this area could still support electrical signals that disrupt the regular contractions of the heart’s upper chambers.

Led by Damiano, also chief of cardiac surgery at the School of Medicine and a cardiac surgeon at Barnes-Jewish Hospital, the Washington University surgeons revolutionized AF treatment in 2002 by helping develop a radiofrequency clamp that creates the ablation lines needed to reroute electrical impulses in the heart. The clamp directs radiofrequency energy into the heart muscle and creates a full-thickness scar.

The radiofrequency clamp procedure is quicker and easier than the original “cut and sew” Cox-Maze procedure, which was developed by James Cox, M.D., at Washington University in 1987. The original procedure relied on a complex series of 10 incisions in the heart muscle, creating a “maze” to channel errant electrical impulses where they should go. In the newer version, called Cox-Maze IV, most of these incisions were replaced by radiofrequency ablations, reducing the operation from an average of 90 minutes to about 30 minutes.

The current study involved two groups of patients with AF. One group underwent radiofrequency ablation-assisted Cox-Maze IV procedures without a box lesion and the other with a box lesion. The box lesion group had a 48 percent lower occurrence of atrial flutter and fibrillation in the first weeks after surgery. These patients also had shorter hospital stays (nine days on average) than patients who had the standard Cox-Maze IV procedure (average stay of 11 days).

Three months after surgery, 95 percent of patients who had the box lesion had no signs of AF, while only 85 percent of the patients who had the standard Cox-Maze IV procedure were free from AF. By six and 12 months postsurgery, all of the patients in the box lesion group were free from AF compared to 90 percent of the other group, although that difference was not statistically significant.

“We also saw that the use of antiarrhythmic drugs was lower after three and six months in those who received a box lesion,” Damiano says. “These drugs can have serious side effects, and if patients can stop using them they often feel better. Overall, the use of the box lesion set was associated with shorter hospitalization, fewer medications and reduced recurrence of atrial fibrillation. We were very pleased with these results.”

Compared to those without atrial fibrillation, people with the disorder are five times more likely to suffer from stroke and have up to a two-fold higher risk of death. For some patients, medications can control the abnormal heart rhythms and the risk of clotting associated with atrial fibrillation, but unlike the Cox-Maze procedure, the drugs usually do not cure the disorder.

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A breast cancer patient’s age alone should not determine whether or not she receives standard breast-conservation treatments, including a lumpectomy and radiation therapy; however, if additional health problems (comorbidities) are present, treatments should be individualized based on age and the type of comorbidities, according to a study in the April 1 edition of the International Journal for Radiation Oncology Biology Physics, the official journal of the American Society for Therapeutic Radiology and Oncology.

The occurrence of breast cancer in women increases as women age. According to the National Cancer Institute’s SEER Cancer Statistics Review, women between the ages of 75 and 79 have the highest incidence of breast cancer diagnoses at 497 cases per 100,000 people. Along with cancer, most women in this age group are dealing with additional health problems. According to a 1999 women’s health and aging study in the Journal of Clinical Epidemiology, the majority of older patients diagnosed with cancer have at least one other medical condition and more than half of patients with cancer over the age of 65 have three or more associated medical conditions.

This study, conducted by the departments of Radiation Oncology, Biostatistics and Epidemiology, and Medicine, Division of Geriatrics, at the University of Pennsylvania School Of Medicine in Philadelphia, sought to determine the impact of these additional medical problems on breast cancer patients who receive the same standard treatments as patients with no additional medical problems and if old age is a reason to deny some standard treatments.

Most randomized trials that compare outcomes of breast-conserving surgery with and without radiation consistently show more positive outcomes when radiation is used; however, most of the trials exclude women older than 70 years old so there is not a lot of data on the impact of radiation on older women.

Between 1979 and 2002, 238 women, 70 years old and older, with Stage I or II invasive carcinoma of the breast received breast-conservation therapy and their outcomes were compared by age groups and comorbidities. Most of the patients studied had mild comorbidities.

The researchers found that the number of deaths from breast cancer among the patients studied was similar to the number seen among all age groups of patients without additional medical problems. The researchers also found that the majority of elderly women with early-stage breast cancers and mild comorbidities actually benefited from the use of radiation and had minimal side effects.

The overall survival rates for the patients in the five- and 10-year follow-up periods were 80 percent and 50 percent, respectively; however, more deaths during the 10-year period were caused by intercurrent diseases than breast cancer.

“Doctors need to understand that comorbidities should be the determining factor in deciding an older patient’s course of treatment, not age,” said Eleanor Harris, M.D., clinical director of radiation oncology at the Moffitt Cancer Center in Tampa, Fla. “There is a sense in the field that elderly women need less treatment than younger women, but we should not be under treating women simply because they have passed the age of 70.”

ASTRO is the largest radiation oncology society in the world, with 9,000 members who specialize in treating patients with radiation therapies. As the leading organization in radiation oncology, biology and physics, the Society is dedicated to improving patient care through education, clinical practice, advancement of science and advocacy.

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A review of research examining the effectiveness of different obesity treatments has concluded that no matter what other forms of therapy are offered, changes in lifestyle are imperative if patients want to maximise and maintain their weight loss. This review, presented at the annual Society for Endocrinology BES meeting in Harrogate, shows that lifestyle interventions provide benefits at all stages of obesity management and should be encouraged no matter what other forms of therapy are offered.

He found that when weight loss drugs are given on their own, with no other changes in lifestyle, they produce an average weight loss of 5 kg, the same amount of weight you lose if you go on a calorie-controlled diet and take regular exercise. However, if weight loss drugs are offered in combination with behavioural therapies, their effectiveness can be increased by over 100% (from 5 kg to 12 kg average weight loss). He found that the story was the same with bariatric surgery. Patients who exercise and lose weight prior to surgery are less likely to have postoperative complications and lose more weight at a quicker rate after surgery than those who didn’t.

Overall, this review indicates, that when treating obese patients, weight loss drugs and bariatric surgery are significantly more successful if they are offered in conjunction with improvements to diet and exercise.

Full results of the review are:

- Exercise alone produces an average weight loss of 1.8 kg. The more you exercise the more weight you lose.

- Diet alone produces an average weight loss of 5.0 kg. This effect peaks 6-12 months following the start of the diet and wanes after this point. No diet is better than any other in the long term but the greater the reduction in calories, the greater the initial weight loss.

- Behavioural therapies (e.g. cognitive therapy, psychotherapy, relaxation therapy, hypnotherapy) produce an average weight loss of 2.3 kg.

- Exercise plus diet result in an average weight loss of 10.7 kg and helps to maintain weight loss for a longer period.

- Exercise plus diet plus behavioural therapies result in the greatest average weight loss of 12-15 kg.

- Taking weight loss drugs with no changes in lifestyle result in an average weight loss of 5kg. Taking weight loss drugs, in combination with behavioural therapies, leads to an average weight loss of 12 kg.

- Patients that lose more than 10% of their body weight prior to bariatric surgery are 2.12 times more likely to achieve a 70% loss of excess body weight.

Researcher Dr Rob Andrews said:

“People often forget is that there is no quick fix to obesity. Overeating and decreased activity are the fundamental problems underlying the development of obesity. Any therapy aimed at helping obese patients must have a dietary and exercise component in order to be successful. This review shows that patients who are taking weight loss drugs or have bariatric surgery lose significantly more weight if they combine these treatments with regular exercise and a calorie-controlled diet. Maintaining a healthy, balanced lifestyle is the key to maximising and maintaining weight loss.”

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Penn State scientists are the first to observe in living cells a key step in the creation of adenine and guanine, two of the four building blocks that comprise DNA. Also called purines, the two building blocks are essential for cell replication. The findings, which will be published in the 4 April 2008 issue of the journal Science, could lead to new cancer treatments that prevent cancer cells from replicating by interfering with their abilities to make purines.

The group used cervical cancer cells–which have an increased demand for purines due to their rapid rates of replication–to demonstrate that a group of six enzymes is involved in the creation of purines. “Our research shows that these enzymes form a cluster prior to purine formation,” said Erin Sheets, an assistant professor of chemistry and a collaborator on the project.

Although other researchers had, in the past, studied the enzymes individually in test tubes, no one, until now, had examined the group of enzymes together in living cells. “This is the first time that anyone has used the appropriate technology to look for this kind of complex in a living cell,” said the team’s leader Stephen Benkovic, Evan Pugh Professor of Chemistry and holder of the Eberly Family Chair in Chemistry.

Postdoctoral associates Songon An and Ravindra Kumar, from the Benkovic group, studied the enzyme clusters using a technique called fluorescence microscopy, in which fluorescent proteins are attached to molecules of interest and viewed under a special microscope. According to Sheets, the technique makes it easier to observe specific molecules in a cell. “It’s like giving a bright orange helmet to your favorite football player so you can more easily monitor his actions,” she said.

The researchers attached fluorescent proteins to the enzymes of cells grown in the presence and absence of purines. They found that in the absence of purines, enzymes formed clusters at much higher rates, suggesting that they play a role in the creation of new purines. In contrast, cells also can produce purines by recycling old purine material. Owing to this salvage process, cells do not always need enzyme clusters; indeed, cluster formation was not observed in cells that were grown in the presence of purines. In a key experiment, the researchers were able to influence the association and dissociation of the enzyme cluster by changing the cells’ exposure to purines.

Not all of the cells that were grown in the absence of purines contained enzyme clusters. “We think that the enzymes form clusters only when a cell needs purines, and that happens when a cell is required to replicate its DNA at a certain stage in its cell cycle,” said Sheets. “Since each of our samples contain cells at different stages of the cell cycle, we did not expect all of them to be actively replicating their DNA. Therefore, we weren’t surprised to find that some of our cells did not contain enzyme clusters.”

Because purines are necessary for DNA replication and, ultimately, for cell replication, the ability to halt purine synthesis could prove to be a valuable method for treating cancer. “Cancer cells have very high demands for purines,” said Benkovic. “If we can find a way to disrupt the formation of this particular enzyme cluster, it could become a potential new target for cancer therapy.”

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