**BIOTECH AND PHARMA NEWS**

[Preciouslife1]

Anti-parasite Drug May Provide New Way To Attack HIV

http://www.sciencedaily.com/releases...0131164715.htm

A drug already used to treat parasitic infections, and once looked at for cancer, also attacks the human immunodeficiency virus (HIV) in a new and powerful way, according to new research.

Past research has established that HIV has "learned" to hide out in certain human cells where it is safe from the body's counterattack, cells that come to serve as viral reservoirs. Operating from these havens, the virus slowly builds its numbers over more than a decade until it finally becomes capable of dismantling human immune defenses. In the end stages, this process leaves patients vulnerable to the opportunistic infections of AIDS.
The newly published work* explains for the first time how the virus makes chemical changes that keep its chosen reservoirs alive long past their normal lifespan. The new study also provides the first evidence that an existing ant-parasite drug can reverse this deadly longevity.

"AIDS continues to take nearly 3 million lives worldwide each year, and novel treatment approaches are urgently needed," said Baek Kim, Ph.D., associate professor in the Department of Microbiology & Immunology at the University of Rochester Medical Center. "We think our results are profound because, in discovering exactly how HIV hides in the body, we think we have learned how to take away its hiding places. Without them, the virus would have a much harder time causing disease," said Kim, lead author of the new study.

Secret to Long Life

Cell division is a process central to life.
A parent cell divides into two cells, each containing
copies of the same genes. This enables a single-cell human embryo to divide and grow into the vast number of cells that make up the human body. Different cell types divide at various speeds. T cells, for example, sense foreign organisms have invaded the body, and quickly divide and grow into a large, specifically designed army to attack the invader.
Macrophages, on the other hand, are designed to roam the body engulfing and digesting dead tissue and bacteria. To assume this special role, they give up the ability to divide.

Unlike most viruses in its family, HIV has the ability to infect both non-dividing macrophages and rapidly dividing T cells, a key to its deadliness. Given its choice, HIV would prefer to infect rapidly dividing T cells, because with each division comes another opportunity for the virus to copy itself using the T cells' genetic machinery. On the other hand, T cells sense they are infected and quickly commit suicide, taking out the virus as well. So quickly do T cells self-destruct that the virus would lose its battle with the human immune system if it did not have long-lived macrophages to hide in during the early years of infection, Kim said.

"""Many cells can "choose" to die when they sense cancer-causing flaws in their own genes, or when they are being used as a virus factory. Certain biochemical pathways call for cell suicide and others postpone it, with the two forces counterpoised to control lifespan. Cancer and AIDS result in part from problems in these pathways."""

Past studies found that HIV-infected macrophages can serve as viral reservoirs because some unknown factor extends their lifespan. In the brain, for example, macrophages secrete toxins produced by the virus they carry, including the transactivator (tat) protein, which causes nearby nerve cells to commit suicide. When enough nerve cells die, patients gradually lose memory, speaking ability and decision-making skills despite the best available treatment.
Presumably, such toxicity should cause brain macrophages to self-destruct as well, but that is not the case. Macrophages live on, and no one had known why until the publication of two papers by Kim's team, one January 30 and the other earlier in January 2007.

The earlier paper reported that macrophages infected with HIV live abnormally long, and that the long life may be related to the presence of the HIV protein tat. In the current study, researchers found the exact mechanism by which HIV turns on a series of cell survival signals in human macrophages: tat-related manipulation of the PI3K/Akt kinase pathway. Phosphatidylinositol 3 kinases (PI3K) are enzymes that turn on another enzyme, Akt, to prevent cell suicide and extend cell lifespan. Akt has been implicated in cancer, where cells live too long.

Kim's team discovered that a molecule called PTEN (phosphatase and tensin homologue deleted on chromosome 10) normally interferes with Akt signaling, and thus, limits cell lifespan. That is unless something interferes with PTEN. In a series of experiments, Kim's team observed that the presence of HIV tat in infected macrophages lowers PTEN levels by 40 percent, enabling the PI3K/Akt pathway to kick back on and keep macrophages alive. The study also found that an existing drug, miltefosine (Impavido®), inhibits PI3K/Akt pathway, and thus, promises to counter the effect of HIV tat on PTEN, Kim said. The treatment was first identified in Germany in the early 1980s as a potential treatment for breast cancer, but is used today to treat a common, parasitic infection called leishmaniasis.

Furthermore, researchers found that HIV-infected macrophages survive longer only when exposed to stress (e.g. toxins secreted by the virus infecting them). Most cells are expendable, and are ordered to self-destruct if exposed to enough stress. The PI3K/Akt pathway, however, kicks on when cells are designed to survive despite surrounding toxicity (e.g. immune cells). Thus, the toxic environment created by HIV ensures the long-term production of HIV within long-lived macrophage reservoirs.

The current study was conducted jointly by the Medical Center and the University of Utah School of Medicine. Along with Kim, joining the effort in Rochester were Pauline Chugh, Birgit Bradel-Tretheway, Sanjay B. Maggirwar and Stephen Dewhurst. Carlos Maximiliano and Vicente Planelles led the effort in Utah.

"Miltefosine puts an end to the long lives of HIV-infected macrophages," Kim said. "The fact that it is already used in humans could accelerate the process of seeking government approval for a new, anti-HIV use for miltefosine, or something like it. In the next phase, we will conduct studies seeking to show that Akt inhibition ends the survival of HIV-infected macrophage reservoirs under real-life conditions."

*This research was published online in the open access journal Retrovirology January 30, 2008.

[Preciouslife1]

How Human T-lymphotropic Virus Can Cause Leukemia In Adults
http://www.sciencedaily.com/releases...0131082244.htm

Researchers have identified a potential new mechanism through which human T-lymphotropic virus type-1 (HTLV-1) causes leukemia in adults. The findings represent the first time that a reduction in histone protein levels has been linked to viral infection and the development of cancer.

HTLV-1 is a retrovirus that causes adult T-cell leukaemia/lymphoma (ATLL). A single protein made by the virus, Tax, is thought to be enough to trigger cancer development.
Tax has a number of effects in the cell, including promoting inappropriate cell division, repressing DNA repair mechanisms and causing genomic instability. These effects are thought to combine and cause cancer, although the exact details of the process are unclear.

James Bogenberger and Paul Laybourn from Colorado State University, USA found that the levels of histone proteins and histone transcripts were lower in T-cell lines infected with HTLV-1 than in uninfected cell lines. They also showed that Tax could cause a drop in the levels of histone transcript in uninfected cells.

Histone proteins are required for the packaging of DNA in cell nuclei and are involved in many key processes associated with DNA, including transcription, repair and replication. The authors suggest that Tax uncouples cell division and replication-dependent histone gene expression, allowing cell division to continue while the levels of histone protein fall.

They write: "We suggest Tax repression of replication-dependent histone gene expression will result in reactivation of viral gene expression, deregulation of cellular gene expression and genomic instability. All of these effects may contribute to the development of adult T-cell leukemia/lymphoma. To our knowledge, this is the first example of a reduction of histone levels correlating with viral infection and cancer development."

Journal reference: Human T-Lymphotropic Virus Type 1 Protein Tax Reduces Histone Levels. James M Bogenberger and Paul J Laybourn. Retrovirology (in press) http://www.retrovirology.com/*******...********/5/1/9

[Preciouslife1]

A biotech feeding frenzy predicted again.

http://money.cnn.com/2008/02/01/news...ce=yahoo_quote

Big Pharma's leaky pipeline
Merck, Amgen, Lilly have some of the most significant pipelines in the industry - and some of the most significant problems.
By Aaron Smith, CNNMoney.com staff writer
February 1 2008: 3:15 PM EST


NEW YORK (CNNMoney.com) -- After the latest round of mixed earnings from the biggest players in pharma and biotech, companies are hampered by a frustrating dynamic: a product mix that isn't strong enough to match an exodus of blockbusters.

Most of the leading drug companies have "weak pipelines" and "huge products going off patent," said Jon LeCroy, pharma analyst for Natixis Bleichroeder. Drugs with $20 billion worth of annual sales are expected to lose patent protection in 2008, according to IMS Health, putting enormous pressure on the industry with a flood of generics.

And the companies with the most significant near-term pipelines - Merck & Co., Amgen and Eli Lilly & Co. - also have some of the most significant challenges.

Merck: Moving past Vioxx
Compared to other drugmakers, many analysts say Merck (MRK, Fortune 500) shows the most promise in the coming year. The company's $4.85 billion Vioxx settlement, announced last November, resolved most of the lawsuits associated with the discontinued arthritis painkiller. But Merck also has two experimental drugs that are awaiting decisions from the Food and Drug Administration: the cholesterol-controlling Cordaptive, and the diet drug taranabant.

Analysts tend to be bullish on Cordaptive as a potential blockbuster that could someday compete with Pfizer's (PFE, Fortune 500) Lipitor - the world's top-selling drug that will go off patent in 2010. Les Funtleyder of Miller Tabak and James McKean of Atlantic Equities both believe Cordaptive could reach $1 billion in annual sales within five years.

But taranabant's prospects are less certain, and analysts are reluctant to provide sales estimates, mainly because it's in the same drug class as Sanofi-Aventis' (SNY) rimonabant. Sanofi pulled rimonabant out of the review process after it was rejected by FDA advisors in 2006, despite its availability in Europe. Some analysts fear that taranabant awaits the same fate.

Merck and its partner, Schering-Plough (SGP, Fortune 500), also face a tough challenge with their combination cholesterol drug Vytorin. On Jan. 14, the companies released a study saying that Vytorin is no more effective at reducing arterial plaque than its cheaper generic component Zocor. Each company's stock has plunged at least 20% since Jan. 14, despite their extensive ad campaigns saying they "stand behind" the drug's safety and effectiveness.

Lilly and prasugrel
Lilly (LLY, Fortune 500) is also banking on FDA approval this year for prasugrel, an experimental anti-clotting drug. If approved, it would compete with Bristol-Myers Squibb's (BMY, Fortune 500) anti-clotting drug Plavix. But it also faces an uncertain future, and many analysts have backed away from their blockbuster projections.

In November, Lilly released a study showing that prasugrel was significantly more effective at preventing blood clots than Plavix. But it was significantly more dangerous in exacerbating bleeding - a side effect of both drugs. Lilly's stock has been up and down since the release of the study.

Amgen and d-nab
Biotech Amgen's (AMGN, Fortune 500) pipeline contains denosumab, an experimental osteoporosis drug that could someday compete with Merck's Fosamax, which loses patent protection on Feb. 6.

Amgen released study results on Jan. 24 showing that denosumab is more effective than Fosamax in treating bone disease of the hips. Bret Holley, analyst for Oppenheimer & Co., projects $2 billion in annual peak sales for the drug.

Also on Jan. 24, Amgen released an unexpectedly strong earnings report and the stock has edged up 4% since that time.

But Amgen's stock lost one-third of its value in 2007, primarily because of ongoing safety concerns over its blockbusters Aranesp and Epogen, which are used to ward off anemia, a side effect of chemotherapy. In 2007, the FDA toughened the warning labels to reflect the potentially fatal side effects of taking high doses of these drugs. The warning also applied to Johnson & Johnson's (JNJ, Fortune 500) Procrit, a member of the same drug class.
The FDA plans to hold another meeting on the safety of these drugs in the next few months.

[Preciouslife1]

Takeda Acquires Amgen’s Japanese Subsidiary

[The acquisition includes the Japanese rights to Vectibix, AMG 706 (a small-molecule angiogenesis inhibitor), and several undisclosed biologics in AMGN’s pipeline in various indications. It also makes Takeda a 50/50 partner with AMGN for AMG 706 outside Japan. Posted by Dew D on BV board.]

http://biz.yahoo.com/bw/080204/20080203005090.html?.v=1
Monday February 4

Amgen and Takeda Announce Exclusive Collaboration in Japan on up to 13 Amgen Clinical Candidates

Amgen to Receive $200 Million Upfront Payment, $702 Million in Multi-year Global R&D Expense Sharing and Success-based Milestones, and Double Digit Royalties on Japan Sales; Takeda Will Receive Exclusive Rights to Develop and Commercialize Select Molecules in Japan .

Deal Includes Global Partnership for Motesanib Diphosphate, which Provides Amgen with an Additional $100 Million Upfront Payment, $175 Million in Success- based Milestones for First 2 Indications, Double Digit Royalties on Japan Sales, and 50/50 Profit Sharing Outside of Japan.

THOUSAND OAKS, Calif. & OSAKA, Japan--(BUSINESS WIRE)
Amgen (NASDAQ:AMGN ) and Takeda Pharmaceutical Company Limited (TSE: 4502) today announced an agreement under which Takeda will develop and commercialize for the Japanese market up to 13 molecules from Amgen’s pipeline, one of which is included as an option. This collaboration validates the significant value of Amgen’s clinical stage pipeline and further ensures Japanese patients will have access to Amgen’s innovative potential medicines for serious illnesses. The collaboration includes early to mid-stage clinical-stage candidates across a range of therapeutic areas, including oncology, inflammation, and pain.

The financial terms include an upfront cash payment to Amgen of $200 million. Takeda will also pay to Amgen up to $340 million in expected worldwide development costs for these molecules over the next several years, $362 million in success-based milestone payments, and double digit royalties on sales in Japan. Additionally, Takeda plans to acquire all the shares of Amgen’s Japanese subsidiary, Amgen KK. We anticipate the share transaction to close in the first quarter.

In addition, Takeda will become Amgen’s worldwide partner for motesanib diphosphate (AMG 706), and will pay Amgen $100 million upfront, $175 million in success-based milestones for the first two indications, and double digit royalties on sales in Japan. Takeda will also pay 60 percent of ongoing clinical development expenses outside Japan and share potential profits outside Japan 50/50.

“We are excited about the agreements with Amgen, and also to welcome Amgen KK into Takeda Group,” said Takeda President Yasuchika Hasegawa. “The target indications of the molecules we licensed from Amgen, such as cancer and bone/joint diseases, are in our core therapeutic areas. We believe they will enhance our R&D pipeline and we are looking forward to offering novel treatment options to the patients with such diseases and to physicians as early as possible, through conducting development activities in close collaboration with Amgen.”

“The development programs included in this collaboration represent the growth engine for Amgen in the next decade,” said Amgen Chairman and CEO Kevin Sharer. “Takeda’s confidence in these programs validates their potential to become innovative therapies for patients in Japan and worldwide. We value and respect Takeda’s strong development and marketing capabilities and look forward to working with the leading pharmaceutical company in Japan.”

The partnership includes Amgen’s Vectibix™ (panitumumab), motesanib diphosphate and additional molecules in oncology, inflammation and neurology/pain. With the exception of oncology candidate motesanib diphosphate, all molecules included in the partnership are biologics. Amgen retains certain co-promotion rights in Japan on all programs.

Financial guidance previously provided on Jan. 24, 2008 by Amgen for 2008 adjusted earnings per share will remain unchanged by this transaction.

About Amgen

Amgen discovers, develops and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science’s promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people’s lives. To learn more about our pioneering science and our vital medicines, visit www.amgen.com.

About Amgen KK

Amgen KK was established March 26, 1992 as a wholly owned subsidiary of Amgen Inc.

About Takeda

Located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders in the industry, Takeda is committed to striving toward better health for individuals and progress in medicine by developing superior pharmaceutical products. Additional information about Takeda is available through its corporate website, www.takeda.com.

[Preciouslife1]

Recurrent Brain Cancer Responds To New Treatment

http://www.sciencedaily.com/releases...0229172028.htm

(Mar. 4, 2008) — One of the toughest cancers to treat effectively is glioblastoma multiforme (GBM), the most common form of primary brain cancer. Patients who have a recurrence of this cancer have had no effective therapy -- until now. Researchers at the University of Virginia and several other leading brain tumor centers nationwide have discovered that a compound has shown the ability to effectively treat GBM in some patients. Vascular endothelial growth factor (VEGF) has an important biologic role in this disease in fostering tumor growth by facilitating the growth of new blood vessels to feed the tumor. According to earlier studies, bevacizumab (BV), a humanized monoclonal antibody that specifically targets VEGF, in combination with irinotecan (also called CPT-11) could have a role in recurrent glioblastoma multiforme. The researchers set out to determine the clinical benefit of BV, both alone and in combination with CPT-11, in a multicenter, randomized phase II trial. The results, presented in late 2007 at the 12th annual Society for Neuro-Oncology meeting, were indeed promising for such an intractable disease. Study results substantially exceeded the pre-specified thresholds set for this work.
The primary endpoints were 6-month progression-free survival (PFS) defined as no clinical or MRI tumor growth and the objective response rate (ORR), which measures tumor shrinkage. Secondary endpoints included safety and survival. Response assessments were conducted by a blinded (without access to data on who took which drug(s)) and independent radiographic facility. All patients were followed for 24 weeks to determine efficacy and safety.
Evaluators at this independent facility assessing found that, when taking BV, 35.6 percent of patients on average had a 6-month survival with no progression of their cancer, and an objective response rate of 21.2 percent on average.
The combination of BV and CPT was even more effective, with results of 51 percent and 34.1 percent, respectively.
“Bevacizumab, taken alone or in combination with irinotecan, is well tolerated by most patients,” said Dr. David Schiff, co- director of the UVA Neuro-Oncology Program. “The drug is active in recurrent glioblastoma multiforme that has failed to respond to any prior therapy.”
The investigator group found similar results when they evaluated the patients. Those results showed that 44.7 percent of patients on average had a 6-month survival with no progression of their cancer, and an objective response rate of 38.8 percent on average. The combination therapy yielded results of 60.9 percent and 46.3 percent, respectively.
Patients on the study are still being treated and followed so that longer-term results will become available.
Known also by its brand name, Avastin, bevacizumab has already been approved for the treatment of me.tastatic colon cancer and most forms of me.tastatic non-small cell lung cancer.
In addition, UVA is planning and conducting additional brain tumor clinical trials with bevacizumab and other anti-VEGF agents.

[Preciouslife1]

PhytoMedical's next-generation compounds effective against cancer cells

Datamonitor Pharmaceutical and HealthWire - Mar. 04, 2008


PhytoMedical Technologies has reported positive results from new tests of the company's next generation anticancer compounds, which have demonstrated the ability to kill difficult-to-treat human cancer cells, including colon cancer cells and human glioblastoma cells related to brain cancer.

In important tests against a difficult-to-treat strain of human colon cancer cells (HCT116), scientists evaluated the performance of concentrated amounts of company's newest anticancer compounds. Researchers observed a 50% or greater cancer cell kill rate using these patented compounds, reporting excellent success in the company's second Phase tests where they have employed new, synthetic bis-acridines for the first time.

Greg Wujek, president and CEO of PhytoMedical, said: "Based on encouraging outcomes from early Phase one research into our first-generation anticancer compounds, we immediately bolstered our efforts and initiated tests of our next-generation compounds. These Phase two tests were specifically designed to target difficult-to-treat strains of human cancer cells, and the resulting outcomes have been very favorable."

[Preciouslife1]

NEWLY IDENTIFIED GENETIC VARIATIONS MAY AFFECT BREAST CANCER RISK


National Institutes of Health Documents and Publications - Mar. 04, 2008

U.S. Department of Health and Human Services
NATIONAL INSTITUTES OF HEALTH NIH News/National Cancer Institute (NCI)

NEWLY IDENTIFIED GENETIC VARIATIONS MAY AFFECT BREAST CANCER RISK

Researchers have identified genetic variations in a region of DNA that may be associated with risk for breast cancer. Women with the variation have a 1.4 times greater risk of developing breast cancer compared to those without this variation. The study is one of several genome-wide association studies looking for breast cancer genes to be published this year by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, and their colleagues. These findings appeared online in the "Proceedings of the National Academy of Sciences" on March 3, 2008.

"A genome-wide association study looks at the entire genome for a type of genetic variation that occurs more frequently in people who have a certain disease than in similar people who do not have the disease," said Bert Gold, Ph.D., of NCI's Center for Cancer Research, the study's lead author. "Using this research approach, we found variations in a gene locus, a specific place on a chromosome where a gene is located, that had not been identified in previous studies.

Genome-wide association studies look for genetic variations known as single nucleotide polymorphisms (SNP).
SNPs are alterations in the genetic code in which a single nucleotide -- the individual building blocks that make up DNA -- is changed. The researchers found that variations in four SNPs located in a region of chromosome 6 were present more often in the breast cancer patients, suggesting that genes in this region might contribute to the risk of breast cancer.
The researchers also confirmed the finding of previous studies indicating that the locus named FGFR2 is associated with a 20 percent increased risk of breast cancer.

"The likelihood that this finding could be due to chance alone is about one in 300 million," said Gold. "We have already begun experiments to try to identify the genes associated with risk, and then try to characterize their function. It is hoped that identifying the genes responsible for this increased risk may lead to new therapies that target the actions of these genes.

"Progressing from genome-wide association studies to the development of therapies and enhanced diagnostic techniques based on those findings will require continued, sustained effort from laboratory researchers who will unite our newfound knowledge of the genome with the study of cancer biology," said NCI Director John E. Niederhuber, M.D.

Several genes located in this chromosome region play a role in regulating important cell processes, such as cell cycle, DNA replication and repair, cell signaling, and programmed cell death. Defects in these processes have been well documented in breast cancer.

While the variations in chromosome 6 that increase risk for breast cancer were found in 23 percent of the women studied, their risk of developing breast cancer is relatively small compared to the high-risk associated with BRCA gene mutations. BRCA genes were identified in the 1990s and mutations in these genes are among the strongest known genetic risk factors for breast cancer. The researchers estimate that only about seven percent of breast cancer cases in this current study could be attributed to the locus they found on chromosome 6.

"Although identifying individual low risk loci may have limited clinical implications, it is not known whether interactions among multiple loci will put a woman at greater risk of developing breast cancer," said Gold. "A better understanding of the genetic mutations that contribute to breast cancer is likely to come from the identification of these low risk variants and from studies that investigate the mechanisms underlying their associations.

The researchers conducted a three-phase genome-wide association study to look for SNPs that may be associated with breast cancer risk. In the first phase, they analyzed more than 150,000 SNPs in DNA samples obtained from 249 Ashkenazi Jewish women who had breast cancer and a family history of the disease but did not carry the BRAC1 or BRAC 2 mutation and from 299 Ashkenazi Jewish women who had not developed cancer. They studied Ashkenazi Jewish women because many studies have demonstrated that this population has been associated with an increased breast cancer risk compared to other populations. In the next two phases, the researchers verified their findings
in 950 Ashkenazi Jewish women with breast cancer and 979 Ashkenazi Jewish women who did not have cancer as well as in a set of 243 Ashkenazi Jewish women who had sporadic breast cancer and 187 cancer-free Ashkenazi Jewish women.

The study participants indicated that all four of their grandparents were Jewish and of Eastern European descent.
The study was designed and directed by a research team at Memorial Sloan-Kettering Cancer Center in New York, with participation from other centers in the United States, Canada, and Israel. In addition to the study coordinating center at Memorial Sloan-Kettering, this study was a collaboration between the NCI and researchers at Memorial Sloan-Kettering Cancer Center, New York, N.Y., Dana-Farber Cancer Institute, Boston, Mass., Tel-Aviv University, Tel-Aviv, Israel, Centre for Research in Women's Health, Toronto, Canada, North Shore Long Island Jewish Research Institute, Manhasset, N.Y., SAIC-Frederick, Inc., Frederick, Md., University of Chicago, Chicago, Ill., Cornell University, Ithaca, N.Y., and Memorial Health University Medical Center, Anderson Cancer Institute, Savannah, Ga.

For more information on research in Dr. Gold's group, please go to http://ccr.cancer.gov/staff/staff.asp'profileid=7351.

For more information about cancer, please visit the NCI website at http://www.cancer.gov, or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov. -----------------------------

REFERENCE:

Gold B, Kirchhoff T, Stefanov S, Lautenberger J, Viale A, Garber J, Friedman E, Narod S, Olshen A, Gregersen P, Kosarin K, Olsh A, Bergeron J, Ellis N, Klein RJ, Clark AG, Norton L, Dean M, Boyd J, and Offit K. March 2008. Genome Wide Association Study Provides Evidence for a Breast Cancer Risk Locus at 6q22.23. "PNAS". Online March 3, 2008.

[Preciouslife1]

A drug that kills cancer cells, spares others

Indo-Asian News Service - Mar. 04, 2008
Report from Indo-Asian News Service brought to you by HT Syndication.

Washington, March 4 -- It has not exactly been the medical *************************alent of the hunt for the holy grail, but scientists have for long been looking for a drug that kills cancer cells and spares healthy ones. And the goal appears within sight.
People get cancer because a protein called p53 - which is supposed to suppress tumours - is not doing its job. About half the time, this is because the gene that holds the protein is mutated or missing altogether.

The rest of the time, another protein, called the human MDM2, is the culprit. It binds to p53 and inhibits its tumour suppressor function, promoting cancer development.

For over a decade, scientists have been searching for ways to block the inhibition of the p53 protein - but in vain.

Now, researchers at the University of Michigan say they have designed a small molecule, called MI-219, which effectively blocks interaction between the MDM2 and the p53.

MI-219 specifically kills tumour cells by harnessing the power of p53. In animal models of human cancer, MI-219 completely inhibited tumour growth and appeared to cause no toxicity to animals.

If clinical trials bear out these results, the drug could potentially treat many different types of cancer, say the authors of the study, the findings of which have been published in online edition of the Proceedings of National Academy of Sciences.

"MI-219 is unique in that it is designed to activate p53 without causing DNA damage, specifically killing tumour cells. Indeed, it is highly effective in inhibiting tumour growth and even inducing regression, but it has caused no toxicity to animals at efficacious doses," said researcher Shaomeng Wang.

Besides these plus points, MI-219 can be developed as a oral pill, rather than traditional chemotherapy that must be given intravenously.

"MI-219 needs to be evaluated in human clinical trials for safety and efficacy for cancer treatment since it is a brand new drug," Wang cautioned.

Published by HT Syndication with permission from Indo-Asian News Service.
HTS sk 080304-601855

[Preciouslife1]

Arsenic Aids Tumor Imaging When Joined To Cancer-homing Drug, Researchers Find

http://www.sciencedaily.com/releases...0301214730.htm

(Mar. 5, 2008) — Arsenic linked to a drug that binds to the blood vessels of cancerous tumors provides a powerful imaging agent that could one day allow physicians to detect hard-to-find tumors and more closely monitor cancer's response to therapy, researchers at UT Southwestern Medical Center have found.

The findings, based on animal studies and appearing in the journal Clinical Cancer Research, mark the first time arsenic has been used to label antibodies for the detection of tumors.

Dr. Philip Thorpe, professor of pharmacology at UT Southwestern and senior author of the study, helped create the cancer drug called bavituximab, an antibody that homes in on a specific molecular target on the blood vessels that feed tumors. Bavituximab is being tested in clinical trials to treat solid-tumor cancers in combination with chemotherapy.

"While arsenic has been used as a poison for centuries, the dose of arsenic needed for imaging tumors is about one-millionth of that needed to cause toxicity," Dr. Thorpe said.

"Arsenic-labeled bavituximab appears to be safe."

In the study, Dr. Thorpe and his colleagues injected radioarsenic-labeled bavituximab into rats with prostate tumors. When the bavituximab bound to its target on the the tumor blood vessels, the tag-along arsenic created a "hot spot" that researchers then imaged using positron emission tomography methods. The radioactivity levels produced by the arsenic are comparable to those used in standard, routine imaging procedures in humans. The technique allowed them to locate and capture unusually clear images of the tumors. They also discovered that there was little or no detectable uptake of bavituximab by normal organs, including the liver, a common site where drugs become entrapped.

"We hope to use this technique to detect early tumor deposits that are not visible using other imaging techniques," said Dr. Thorpe. "The images we obtain are so clear that we may be able to see secondary tumors that have spread from the original tumor mass and lodged in distant organs."

The forms of arsenic used in the experiments are called radionuclides, which are radioactive versions, or isotopes, of the element. Several radionuclides currently are used in imaging, but many of the isotopes decay, or breakdown, before they reach the target in the body. The slow rate of decay of arsenic isotopes, together with their stable chemistry, allowed the researchers to couple arsenic to bavituximab and obtain images of the tumors for several days after the drug was given. Optimal tumor imaging in humans is often achieved three days or more after a radio-labeled antibody is administered.

"Long neglected as an awkward Cinderella, arsenic has great potential for new imaging agents and therapeutics based on multiple isotopes with diverse useful characteristics," said Dr. Ralph Mason, professor of radiology, director of the UT Southwestern Cancer Imaging Program and one of the study's authors.

Dr. Mason recently received a grant from the Department of Defense Breast Cancer Initiative to investigate whether arsenic could be used to image breast tumors.

In addition to Drs. Thorpe and Mason, other investigators in UT Southwestern's Harold C. Simmons Comprehensive Cancer Center carried out the research in collaboration with colleagues from UT Austin, Johannes Gutenberg University of Mainz in Germany and the University of Brussels in Belgium. The collaboration included pharmacologists, physicists and chemists.

Other UT Southwestern scientists involved in the study were Dr. Matthew Lewis, assistant professor of radiology; Dr. Dawen Zhao, assistant professor of radiology; Dr. Edward Tsyganov, clinical assistant professor of radiology; Dr. Nikolai Slavine, assistant professor of radiology; Linda Watkins, research scientist in pharmacology; Dr. Vikram Kodibagkar, assistant professor of radiology; and Dr. Peter Antich, professor of radiology.

The research was funded by Gillson Longenbaugh Foundation, National Cancer Institute, Peregrine Pharmaceuticals Inc., Deutsche Forschungsgemeinschaft and the Department of Defense.

Peregrine has exclusively licensed bavituximab from UT Southwestern and has a sponsored research agreement to further explore clinical uses of the drug. Dr. Thorpe is a consultant to and has an equity interest in the company.

Adapted from materials provided by UT Southwestern Medical Center.

[Preciouslife1]

Newly Developed Anti-malarial Medicine Treats Toxoplasmosis

http://www.sciencedaily.com/releases...0304200908.htm

(Mar. 5, 2008) — A new drug that will soon enter clinical trials for treatment of malaria also appears to be 10 times more effective than the key medicine in the current gold-standard treatment for toxoplasmosis, a disease caused by a related parasite that infects nearly one-third of all humans--more than two billion people worldwide.

A research team based at the University of Chicago Medical Center shows that the drug, known as JPC-2056, is extremely effective against Toxoplasma gondii, the parasite that causes toxoplasmosis, without toxicity.

"JPC-2056 has the potential to replace the standard treatment of pyrimethamine and sulfadiazine," said infectious disease specialist Rima McLeod, professor of ophthalmology at the University of Chicago and senior author of the study. "The drug, taken by mouth, is easily absorbed, bioavailable, and relatively nontoxic. In tissue culture and in mice, it was rapidly effective, markedly reducing numbers of parasites within just a few days."

Untreated mice injected with the parasite "appeared ill," four days after the injection, the authors note, "with ruffled fur and hunched shoulders." Treated mice remained well.

"Studies in tissue culture found no evidence of the parasite or the plaques they produce 52 days after four days of treatment," said co-author Ernest Mui, a researcher in McLeod's laboratory.

"The absence of growth," the authors write, "indicates that this compound is 'cidal' and not merely 'static' for the active form of T. gondii.

The drug inhibits the action of an enzyme, dihydrofolate reductase (DHFR), produced by the family of parasites that includes those that cause toxoplasmosis and malaria. It is structurally distinct from the human DHFR.

"The drug's effect on the malaria and Toxoplasma enzymes is robust," said McLeod. "It has much less effect on the human enzyme."

The new drug was effective against all malaria parasites, even those with multiple mutations that make them resistant to other anti-folate medicines, suggesting that "this family of parasites, including not just Toxoplasma but also various malaria parasites, will not easily develop resistance," she said.

Toxoplasma infection is "probably the most common parasitic infection in the world, causing very significant disease in those who have immature immune systems or who are immune-compromised," McLeod said. "New medications are urgently needed."

The standard medicines to treat the infection can cause severe side effects and many patients become hypersensitive to them. There are no medicines that can eliminate certain latent stages of the parasite's life cycle. There is no vaccine.

T. gondii infects humans through three principal routes: a newly infected pregnant woman passing the infection to her fetus; consumption of undercooked, infected meat; and ingestion of T. gondii oocysts in food, through accidental contamination from cat litter.

"An infected cat can excrete up to 20 million oocysts over two weeks," McLeod said. "Even a single oocyst is infectious and they can remain infectious in water for up to six months and in warm moist soil for up to a year."

Congenital toxoplasmosis, which occurs in an estimated 1 per 5,000 births a year in the United States, can cause severe vision loss, brain damage and even death. The annual cost of caring for these children may exceed $1 billion.

Also at increased risk are people with compromised immune systems, such as those with cancer, autoimmune disease, AIDS or transplant recipients. Even people with normal immune systems can suffer major organ damage from chronic infections. Eye disease leading to loss of sight is caused both during the primary infection and as a result of infection transmitted from mother to child. Recent epidemics in Surinam and French Guiana have been lethal even for young healthy victims. Studies have also found an association between chronic brain infection with Toxoplasma and diseases such as schizophrenia and epilepsy, although cause-and-effect relationships have not been proven.

JPC-2056 was developed in the late 1980s by teams led by Wilbur Milhous and Dennis Kyle of the Walter Reed Army Institute for Research in Silver Spring Maryland (both now at the University of South Florida), and David Jacobus of Jacobus Pharmaceutical Company. The original version was quite toxic, but the researchers found ways to reduce the toxicity and developed an oral version of the drug. Clinical trials using JPC-2056 to treat malaria are scheduled to begin later this year.

This new class of medicine holds "considerable promise for significant advances in the treatment of toxoplasmosis, which damages the eye and the brain," said McLeod, "as well as malaria, which kills one million children each year."

This research is published in the March issue of PLoS Neglected Tropical Diseases.

[Preciouslife1]

New Colon Cancer Screening Guides Issued

By MIKE STOBBE AP Medical Writer

http://hosted.ap.org/dynamic/stories/C/COLON_CANCER_SCREENING?SITE=AP&SECTION=HOME&TEMPLA TE=DEFAULT&CTIME=2008-03-05-19-32-59

ATLANTA (AP) -- Medical experts recommended Wednesday that a less invasive procedure known as a virtual colonoscopy and a stool DNA test join the arsenal of screenings for colon cancer in the hopes that more people would get checked out.

The recommendations bring to six the number of screening tests suggested for spotting signs of colon cancer, said Dr. Otis Brawley, national chief medical officer of the American Cancer Society, one of the groups that made the recommendations.

The tests range in price from a few dollars to several hundred. Which test is best for patients depend on several factors, including what their insurer covers and the preference of their primary care doctor, experts said.

Only one company has a stool DNA test on the market - EXACT Sciences Corp. of Marlborough, Mass. The medical groups delayed releasing the recommendations until markets closed Wednesday because they were concerned it would affect trading, Brawley said.

The recommendations may also mean more business for radiologists. There has been something of a turf battle between gastroenterologists, who perform colonoscopies, and radiologists, who handle virtual colonoscopies.

The new guidelines represent an agreement that both are valuable ways to diagnose and prevent colon cancer, Brawley said.

These first consensus guidelines were released by the Cancer Society, the American College of Radiology, and the U.S. Multi-Society Task Force on Colorectal Cancer.

The latter group comprises representatives from the American College of Gastroenterology, the American Gastroenterological Association and the American Society for Gastrointestinal Endoscopy.

The recommendations came out the same day as a medical study that found that flat growths on the colon wall are more common in Americans than previously thought. Researchers concluded that the growths are more likely to be cancerous than the more familiar knobby masses known as polyps.

The study, published in the Journal of the American Medical Association, suggested that more careful colorectal cancer screening is necessary.

However, Brawley said the release of the new recommendations was coincidental and not driven by the study's findings.

Colorectal cancer is the nation's second leading cancer killer. It will kill about 50,000 people in the United States this year, the Cancer Society estimates. Screenings are designed to save lives by finding growths before they turn cancerous.

Traditional colonoscopies, long considered the gold standard test, are recommended every 10 years, starting at age 50. A doctor snakes a long, thin tube equipped with a small video camera through the large intestine to view the lining. The doctors also can use the device to cut away a tissue sample or even remove a polyp.

However, colonoscopies come with risks, including a chance that a doctor will accidentally puncture the colon. Also, many people have balked at getting screened because the test is expensive and they perceive it as unpleasant.

A virtual colonoscopy is a sort of super X-ray of the colon and rectum. Air is pumped into the colon to stretch it, and then a special CT scan is done. It is not invasive, but if a polyp is found, doctors will have to perform an optical colonoscopy in order to take a biopsy.

The biggest issue is not which screening a patient should get, but that patients come in for screening. All colon cancer deaths can be averted through screening and early treatment, but only 30 percent of people recommended to get screenings actually do, according to the Cancer Society.

"The challenge we have is getting people to participate in screenings," said Jack Mandel, an Emory University epidemiologist who has studied colon cancer screening tests. "We can prevent these deaths."

[Preciouslife1]

Elevated Liver Enzymes Associated With Higher Future Mortality

http://www.sciencedaily.com/releases...0303110200.htm

(Mar. 5, 2008) — A new population-based epidemiological study has found that elevated liver enzymes discovered during routine medical care are associated with higher future mortality.

Liver enzymes include aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and high concentrations in the blood tend to indicate liver disease. About 10 percent of Americans have an elevated liver enzyme with no evidence of a cause such as hepatitis C or excessive alcohol consumption. Presumably, many cases are due to non-alcoholic fatty liver disease.

Studies in other countries have shown that elevated liver enzymes are associated with future mortality, however the link has never been examined in a U.S. population, so researchers led by Tae Hoon Lee of the Mayo Clinic in Rochester, Minnesota set out to address this question. They used data from Olmsted County, MN, where most of the population has had medical care at Mayo Clinic facilities, and included all adult patients who had their AST or ALT levels measured during routine visits in 1995. Those with levels above the upper limit of normal were followed forward until April 2006 to determine their survival.

AST was measured in 18,401 residents, and 2,350 (13 percent) had results above the upper limit of normal. Of 6,823 people who had their ALT measured, 911 (13 percent) had results higher than the upper limit of normal.

After excluding those who moved away from the community, or died within two years (to rule out terminal illness as the cause of the abnormal liver enzyme levels), the researchers used the Kaplan-Meier method to estimate survival. They compared their results to mortality data for Minnesota Whites and found that elevated AST was associated with a significantly increased standardized mortality rate (SMR). Elevated ALT was also associated with a higher SMR. The SMRs ranged between 1.21 and 1.78.

"We demonstrate that serum AST and ALT activities are associated with increased risk of mortality in the ensuing decade," the authors report. "The relation between the aminotransferase results at the outset and the subsequent risk of death (excluding the first two years) was almost linear. It is clearly shown that these simple, inexpensive blood tests may represent valuable indicators of long-term outcome."

While the precise reasons for the association are unclear, some in the population undoubtedly had elevated enzymes as a result of serious liver disease. In addition, the authors suggest that elevated serum AST and ALT may be markers of cardiovascular diseases (nearly 34 percent of the deaths in the study population were due to cardiovascular causes). Other conditions such as chronic alcohol consumption or abuse may have contributed to the risk of death as well.

They study had limitations. First, the population was not a random sample and they were community residents who had reasons for receiving medical care. Second, their aminotransferase levels were only measured once. Lastly, they were mostly Caucasian, reducing the generalizability of the data. Still, the findings are strong.

"These data, based on a large number of residents in a U.S. community, suggest that serum levels of AST and ALT obtained in a routine medical care setting are associated with future mortality," the authors conclude.

Article: "Serum aminotransferase activity and mortality risk in a United States community." Lee, Tae Hoon; Kim, W. Ray; Benson, Joanne; Therneau, Terry; Melton, III, L. Joseph. Hepatology; March 2008.