Posted by rob on February 27, 2006 under Uncategorized | 
| When a blood test in 2000 showed he had chronic myelogenous leukemia, Bryce Morgan first called a doctor friend.
Next, he went online.
Morgan used the Internet to check out his oncologist’s qualifications, to decide where to undergo his bone-marrow transplant and to learn what to expect during his recovery.
“It took the fear out,” said Morgan, 51, a computer consultant from Buffalo. “I felt like I was in control of my destiny, as much as I could be.”
Morgan is one of a growing number of people in Western New York and across the country using the Internet to research diseases, alternative treatments and new drugs.
Patients say this online research makes them feel like a partner with their doctor.
“It helps me have a conversation with an educated partner, even if some of that information is a little askew,” said Dr. Thomas C. Rosenthal, chairman of the family medicine department at the University at Buffalo School of Medicine and Biomedical Sciences.
Internet surfing replaced the digging that patients had to do in libraries 10 or 20 years ago.
Those not able to devote the time to search a library’s shelves had to rely on anecdotal information from a relative or co-worker. But people back then were more reluctant to talk about an illness such as cancer, doctors noted.
For the most part, only doctors had access to journal articles or data from clinical trials, so the doctor-patient relationship tended to be paternalistic.
That has changed, in large part as a result of the Internet.
Seventy-nine percent of Internet users say they have gone online to research at least one health topic, according to a 2005 survey by the Pew Internet & American Life Project.
Researchers in UB’s School of Nursing surveyed 20 female cancer patients about how they used the Internet.
“[Internet research] changes it from a death sentence to an idea that it’s a chronic illness, something to be dealt with,” said Suzanne S. Dickerson, a UB associate professor of nursing and principal investigator on the study, published in the Oncology Nursing Forum.
Dr. Irene S. Snow, medical director of the Buffalo Medical Group, said that, five years ago, only one of the 20 patients she saw each day in her Williamsville office would ask a question based on online research. Today, it’s at least one in four, she said.
Doctors’ reluctance
Not every doctor is thrilled when patients bring up a second opinion from a Web site.
“Some doctors resent the patients coming in with this information. We see that,” said Bill McLaughlin, 77, a Clarence resident and leader of the Buffalo metro area chapter of Us TOO, a prostate cancer education and support network.
Marcia Heaney, diagnosed with breast cancer in 2001, said the first oncologist she consulted simply told her what to do.
She sought a second opinion from another oncologist, who urged her to take her time in researching and considering all the possible treatments.
“There are a number of different options for treatment, and you need to be an educated consumer,” said Heaney, president of the Breast Cancer Network of Western New York.
Patients tend to ask more and better questions after online searches, said Dr. Judy L. Smith, a surgical oncologist and medical director at Roswell Park.
“It makes the physician’s job easier,” she said.
With thousands of medical Web sites, how reliable is the information available online?
Physicians and medical experts said the Web sites vary considerably, so patients need to consider the source of the information on each site.
Those experts said reputable sites include WebMD.com,
Family-Doctor.org and MedLinePlus.gov, as well as the disease-specific sites of groups like the American Diabetes Association.
One feature on the WebMD site allows visitors to indicate their symptoms – using a model of a human body – and to get a possible diagnosis in response. But, a note cautions: “This information is not intended to replace the advice of a doctor.”
Dr. James G. Corasanti said the Internet is useful as long as patients don’t use it to self-diagnose their ailment.
“[Patients] know what’s being done at [the Mayo Clinic], Cleveland Clinic. They demand excellence, which is good,” said Corasanti, medical director of the gastrointestinal laboratory at Buffalo General Hospital.
Caution urged
Morgan, the computer consultant, said his search showed that his oncologist had published 15 papers in the previous nine years.
“I read them all,” Morgan said.
Joan Morrissey moved to Snyder two years ago from Atlanta, where she worked as a health communicator for the Centers for Disease Control. Her job involved steering callers to credible online sources of information.
On Easter Sunday 2004, Morrissey awoke to find her right breast red and painfully swollen. She soon learned she had inflammatory breast cancer, a rare form of the illness.
Her cancer is now at the advanced stage 4, and further options for treatment are limited.
At the online recommendation of another patient, Morrissey is taking Avastin, a drug that limits the growth of cancer cells by stopping the production of new blood vessels, and Taxol, a traditional chemotherapy drug.
She said she uses the Internet judiciously.
“Sometimes I get on there, and it gives me encouragement. And sometimes you get trapped, just by reading [patient diaries], and I get depressed,” said Morrissey, 42.
Nancy Kelly also said she avoided reading patient diaries, preferring to get hard information that will help her with her own fight against melanoma.
“The Internet is incredibly frank, not that you need all that information every day,” said Kelly, 57, a South Buffalo resident and retired county worker who volunteers at Roswell Park.
A number of well-meaning sites also might have inaccurate information.
Patients also need to be cautious with sites that have a financial motivation, all agreed.
Rosenthal, the chairman of UB’s family medicine department, recalled a pediatric patient whose mother initially wanted to treat her son’s condition with a natural supplement instead of prescription medicine. The same site recommended and sold the supplements, Rosenthal said.
The digital divide between those who can afford access to the Internet and those who can’t also remains an issue.
Doctors with primarily suburban practices said their patients regularly use the Internet.
Dr. Chester H. Fox, a physician with the Jefferson Family Medicine Clinic in Buffalo, said his patients largely do not, and he is unable to recommend Web sites where they can do research.
Other doctors note patients have access to computers in area public libraries. And Roswell Park, for example, offers Internet access at a cancer resource center and on laptops that patients can take to their rooms.
The hospital also has set up three computer kiosks where patients can look up and print out information provided by the National Cancer Institute.
e-mail: swatson@buffnews.com
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Buffalo News – Patients turn to Internet to battle illness
Posted by rob on February 25, 2006 under Uncategorized |
K562 is the chronic myelogenous leukemia (CML)-derived cell line that expresses high levels of chimeric oncoprotein Bcr-Abl. The deregulated (permanent) kinase activity of Bcr-Abl leads to continuous proliferation of K562 cells and their resistance to the apoptosis promotion by conventional drugs. The photodynamic treatment (PDT) based on the application of 5-aminolevulinic acid (ALA) and irradiation with blue light (ALA-PDT) resulted in the suppression of K562 cells proliferation. It was followed by a necrosis-like cell death [K. Kuzelová, D. Grebenová, M. Pluskalová, I. Marinov, Z. Hrkal, J. Photochem. Photobiol. B 73 (2004) 67-78]. ALA-PDT led to the perturbation of the Hsp90/p23 multichaperone complex of which the Bcr-Abl is the client protein. Bcr-Abl protein was suppressed whereas the bcr-abl mRNA level was not affected. Further on, we observed several changes in the cytoskeleton organization. We detected ALA-PDT-mediated disruption of filamental actin structure using FITC-Phalloidin staining. In connection with this we uncovered certain cytoskeleton organizing proteins involved in the cell response to the treatment. Among these proteins, Septin2, which plays a role in maintaining actin bundles, was suppressed. Another one, PDZ-LIM domain protein 1 (CLP36) was altered. This protein acts as an adaptor molecule for LIM-kinase which phosphorylates and thus inactivates cofilin. Cofilin was indeed dephosphorylated and could thus be activated and operate as an actin-depolymerizing factor. We propose the scheme of molecular response of K562 cells to ALA-PDT.
Photodynamic treatment (ALA-PDT) suppresses the expression of the oncogenic Bcr-Abl kinase and affects the cytoskeleton organization in K562 cells.
Posted by rob on under Uncategorized |
The Philadelphia chromosome (Ph) as a secondary cytogenetic abnormality is a rare event. It is observed mostly as an additional, late-appearing cytogenetic change during the evolution of acute leukemia and its presentation as a secondary change at the onset of disease is much rarer. We describe here a patient with acute myelogenous leukemia (AML) who had Ph as a secondary chromosome abnormality at diagnosis. Cytogenetic analysis showed an abnormal karyotype, 45,XY,inv(3)(q21q26),-7[4]/45,idem, t(9;22)(q34;q11.2)[16]. The p190 variety of BCR-ABL rearrangements was confirmed by a real-time reverse-transcriptase polymerase chain reaction using fluorescent probes. To our knowledge, the minor BCR-ABL fusion gene involving a secondary Ph superimposed on inv(3) and monosomy 7 has not been reported in AML at diagnosis. Along with the identification of more cases, it will be possible to understand the exact role of this secondary Ph in a multistep leukemogenesis.
The Philadelphia chromosome as a secondary abnormality in inv(3)(q21q26) acute myeloid leukemia at diagnosis: confirmation of p190 BCR-ABL mRNA by real-time quantitative polymerase chain reaction.
Posted by rob on under Uncategorized |
Protein tyrosine phosphatase 1B (PTP-1B) is a ubiquitously expressed cytosolic phosphatase with the ability to dephosphorylate JAK2 and TYK2, and thereby down-regulate cytokine receptor signaling. Furthermore, PTP-1B levels are up-regulated in certain chronic myelogenous leukemia patients, which points to a potential role for PTP-1B in myeloid development. The results presented here show that the absence of PTP-1B affects murine myelopoiesis by modifying the ratio of monocytes to granulocytes in vivo. This bias toward monocytic development is at least in part due to a decreased threshold of response to CSF-1, because the PTP-1B -/- bone marrow presents no abnormalities at the granulocyte-monocyte progenitor level but produces significantly more monocytic colonies in the presence of CSF-1. This phenomenon is not due to an increase in receptor levels but rather to enhanced phosphorylation of the activation loop tyrosine. PTP-1B -/- cells display increased inflammatory activity in vitro and in vivo through the constitutive up-regulation of activation markers as well as increased sensitivity to endotoxin. Collectively, our data indicate that PTP-1B is an important modulator of myeloid differentiation and macrophage activation in vivo and provide a demonstration of a physiological role for PTP-1B in immune regulation.
Protein tyrosine phosphatase 1B negatively regulates macrophage development through CSF-1 signaling.
Posted by rob on February 24, 2006 under Uncategorized |
NEW DELHI: The controversy over the introduction of product patents for drugs has come full circle. Gleevec, the much sought-after cancer drug that has been the face of the campaign against the new WTO-compliant patent law, can now be made and sold at more affordable rates by Indian companies.
In its latest journal of February 17, the Indian Patent Office notified the termination of exclusive marketing right (EMR) granted two years ago to Swiss major Novartis for Gleevec.
This follows its decision on January 25, rejecting the application of Novartis for what could have been the first-ever product patent in India for a pharmaceutical drug. It was only last year that product patents were introduced in India for drugs and chemicals complying with the deadline imposed by Trade Related Intellectual Property Rights (TRIPS).
Novartis had been granted EMR for Gleevec in November 2003 in anticipation of the product patent regime that was due to be installed in India by January 1, 2005.
Relief: Cancer drug is out of patent loop- The Times of India
Posted by rob on February 23, 2006 under Uncategorized |
Genzyme Corporation has announced that they have just made a test available to the public that can detect whether a patient with chronic myeloid leukemia (CML) is resistant to treatment with Gleevec® (imatinib mesylate).
Gleevec is the standard treatment for patients with newly diagnosed CML. Over 90% of patients respond well to initial treatment with long-term benefit. However, 5-10% ultimately develop resistance, which is apparently due to secondary mutations of BCR-ABL. The new BCR-ABL Mutation Analysis test may help determine whether a patient is resistant to Gleevec. It tests for specific mutations that are present when a patient does not respond to Gleevec.
Comments: At the present time it is not clear how clinically useful the determination of specific mutations will be in the treatment of Gleevec resistant CML. Understanding of the mechanisms of resistance has led to the development of agents such as dasatinib and AMN107. However, the current paucity of agents available for the treatment of Gleevec resistant disease may limit the clinical utility of specific tests. AT the present time empiric treatment with available drugs is probably the only way to manage Gleevec resistant patients. The BCR-ABL Mutation Analysis may, however, provide insight into disease resistance.
Reference: Genzyme Corporation. Genzyme Launches Key Test To Monitor Gleevec® Resistance. Available at: http://www.genzyme.com/corp/media/GENZ%20PR-020906.asp#TopOfPage. Accessed February 2006.
Related News:
Small Molecule Bcl-2 Protein Inhibitor, GX15-070, Active for Treatment of Refractory Chronic Lymphoid Leukemia (1/12/2006)
Aminopyrimidine Inhibitor, AMN107, Effective for Gleevec®-Resistant Chronic Myeloid Leukemia (11/11/2005)
Vaccine May Eradicate Minimal Residual Disease in Patients with Chronic Myeloid Leukemia (3/2/2005)
Excellent Results of Gleevec® as Initial Therapy of CML Holding Up at 42 Months (12/10/2004)
New Drugs Target Gleevec®-Resistant CML (12/9/2004)
Gleevec® is Safe and Effective for Children with Philadelphia Chromosome-Positive Leukemia (11/3/2004)
Increasing the Dose of Gleevec® Improves Molecular Response Rate in CML (4/13/2004)
Test Now Available to Detect Resistance to Gleevec® in Chronic Myeloid Leukemia
Posted by rob on under Uncategorized |
Dan Berrett
Pocono Record Writer
February 23, 2006
STROUDSBURG — Salli Chacon knew something was wrong with her daughter, Danica.
The girl had been sleeping more than usual. Her mother thought that Danica’s fatigue was due to her earlier wake-up time now that she was attending Stroudsburg Middle School.
By December, Chacon grew worried enough that she got some blood work done for her daughter. The white blood cell count was abnormally high. She had leukemia.
Chacon wrestled with how to break the news to her daughter. The 13-year-old cut to the chase.
“Mommy, I have cancer,” she said, according to her mother. “Am I going to die?”
Since then, the Chacons’ lives have been occupied with the battle against the disease: taking medication and searching for a bone marrow donor.
But they also tried to maintain life as usual. “She hasn’t missed a day of school,” said Chacon. “We’re trying to keep everything normal for her.”
Considering the situation, the family has been fortunate; Danica has responded to her medicine, Gleevec, and her brother, Jayson, 15, is a perfect match for a transplant. She is one of about 2,200 young people in America who are afflicted with leukemia each year; it accounts for about 25 percent of all childhood cancers, according to the National Institutes of Health.
Her classmates and teachers at the middle school have pitched in, too. The student government launched a lollipop sale fundraiser that brought in over $4,400.
The family will likely use the money to defray income it will lose this summer, when Chacon will stop working to stay by her daughter’s bedside after her bone marrow transplant at Children’s Hospital of Philadelphia. The surgery hasn’t been scheduled yet, but the recovery period can take up to three months.
“I really don’t know what to expect,” said Chacon.
The class that raised the most money in each grade received a few prizes. On Tuesday, the winning sixth-grade class had an ice cream party. On Wednesday morning, it got an extra bonus: being taught by the school’s principal, Ray Scarpantonio.
“This is one of the things that you miss the most,” Scarpantonio said to Andrea Link’s social studies class. He led the 24 sixth-graders in a lesson that combined math and American history.
They plotted points on pieces of graph paper while Scarpantonio taught them ordinal and cardinal directions on an overhead projector.
After connecting the dots that they plotted, the students saw that it formed a portrait of George Washington. The rest of the class was spent on a lesson about the first president.
“It was funner than the usual class,” said Ciara Banks, 11, as she gathered her books.
The school’s efforts for Danica Chacon will continue. On April 8, it’s planning to host a bone marrow registry. A blood drive is also in the works.
“This will be a way to show my thanks,” said Chacon. “My daughter was so fortunate because her brother was a perfect match.”
Pocono Record – Sick S-burg student has school spirit
Posted by rob on February 22, 2006 under Uncategorized |
By Alan McClelland
HONOLULU, HI — February 21, 2006 — Researchers have developed an evidence based real-time scoring system for quantitative assessment of acute graft versus host disease (GvHD) activity.
According to George McDonald, MD, Fred Hutchinson Cancer Research Center in Seattle, Washington, United States, presented the acute GVHD activity index model at the 2006 Blood and Marrow Transplantation Tandem meetings (ASBMT).
Current scoring systems for acute GvHD are inadequate due to retrospective assignment of scores, failure to take efficacy of treatment into account and variability between observers, Dr. McDonald explained during his presentation on February 17th.
An improved grading system would help determine prognosis in individual patients and quantify the burden of GvHD over time, he said.
Dr. McDonald and colleagues developed the system by examining and scoring the severity of GvHD symptoms and abnormalities, use of immunosuppressive drugs, and performance status in 386 patients with chronic myelogenous leukemia (CML) who underwent allogeneic hematopoietic stem cell transplantation.
The researchers scored patients at 10 day intervals from the onset of GvHD until day 100 and used data from 191 randomly selected patients to generate an activity index that they say predicts non-relapse mortality at day 200.
Parameters that they found contribute to the predictive value of the model include liver dysfunction (serum bilirubin levels), upper gastrointestinal tract abnormalities (reduced caloric intake, nausea, vomiting), immunosuppressive therapy and performance status.
The investigators tested the accuracy of the model in predicting day 200 non-relapse related mortality against an independent data set of 193 patients and obtained good predictive values comparable to those obtained with the initial data set used to develop the model (area under receiver operator curve of 0.87), Dr. McDonald said.
Advantages of the activity index are that it is evidence based, easy to calculate, can be used in real time and has good predictive value for non-relapse related mortality, he said.
“This score puts an objective number on a subjective clinical observation,” Dr. McDonald said. As such, it should be a useful tool to help clinicians determine when to initiate more aggressive therapy for GvHD and might also be of use for stratification of patients according to risk of mortality in therapeutic trials, he added.
[Presentation title: Determining Prognosis for Patients with Acute GVHD in Real Time; Development and Testing of an Acute GVHD Activity Index. Abstract 29]
News – Acute Graft Versus Host Disease Activity Index Can Be Used to Predict Non-Relapse Mortality: Presented at ASBMT
Posted by rob on February 21, 2006 under Uncategorized |
C.R. Sukumar
| Natco Pharma had challenged the grant of EMRs to Novartis. The grant of EMRs to Novartis had forced several Indian pharmaceutical companies such as Ranbaxy, Cipla, Sun, Hetero, Torrent and Emcure to withdraw their generics from the market. |
Hyderabad , Feb. 21
IN yet another blow to the Swiss pharmaceutical giant Novartis AG in the Indian pharmaceuticals market, the Indian Patents Office has terminated the exclusive marketing rights (EMRs) granted to the company on November 10, 2003 for Gleevac (Imatinib Mesylate), a life saving anti-cancer drug, with effect from January 25, 2006.
Interestingly, on January 25 this year, the Swiss company had lost a patent claim for the anti-cancer drug — Imatinib Mesylate — before the office of the Indian Controller of Patents & Designs, following serious objections through pre-grant opposition route raised by Natco Pharma Ltd, a Hyderabad-based pharma company.
The Controller of Patents had refused to proceed further with Novartis patent application for Gleevac, which is used in the treatment of chronic myeloid leukaemia.
Interestingly, the Indian Patents Office has now decided to cancel the EMRs granted to Novartis based on the same grounds raised by the Office of Controller of Patents & Designs.
Citing the order of Office of the Controller of Patents & Designs dated January 25 in a notification dated February 17, the Indian Patents Office said, “Therefore, as per Section 78 of the Patents (Amendment) Act 2005 read with Section 24B of the Patents Act 1970 as amended by the Patents (Amendment) Act 2002, the said Exclusive Marketing Right granted to Novartis AG is hereby terminated with effect from January 25, 2006.”
Natco Pharma, which launched a generic version of Gleevac under the brand `Veenat’, had challenged the grant of EMRs to Novartis.
The grant of EMRs to Novartis had forced several Indian pharmaceutical companies such as Ranbaxy, Cipla, Sun, Hetero, Torrent and Emcure to withdraw their generics from the market.
Though the price difference between Gleevec and its clones was around twelve-fold, the domestic pharmaceutical companies were restrained from manufacturing and marketing the cheaper clones due to a Court order.
This case is currently pending before the Supreme Court.
The Office of Controller of Patents on January 25 ruled that the patent applied for by Novartis AG did not qualify as an invention on the grounds that it was merely a modification of the key component in the drug, for which a patent had already been filed in 1993.
Therefore, according to the Controller of Patents, this key component can not be eligible for protection under new patent regime of India that was introduced in March 2005 to comply with the WTO agreement on trade related aspects of intellectual property rights (TRIPS) that recognises patents for chemical products filed there after 1995, the year the WTO came into existence.
The Hindu Business Line : Exclusive marketing rights for Novartis’ cancer drug cancelled
Posted by rob on under Uncategorized |
Research could shape new treatments
By NICHOLAS WADE
New York Times
Posted: Feb. 20, 2006
One day, perhaps in the distant future, stem cells may help repair diseased tissues. But there is a far more pressing reason to study them: Stem cells are the source of at least some, and perhaps all, cancers.
At the heart of every tumor, some researchers believe, lie a handful of aberrant stem cells that maintain the malignant tissue.
The idea, if right, could explain why tumors often regenerate even after being almost destroyed by anti-cancer drugs. It also points to a different strategy for developing anti-cancer drugs, suggesting they should be selected for lethality to cancer stem cells and not, as at present, for their ability to kill just any cells and shrink tumors.
“I think this is one of the most interesting developments in cancer research in the last five years,” said Robert Weinberg, a cancer geneticist at the Whitehead Institute in Cambridge, Mass. “I think more and more people are accepting it, and evidence is accumulating that cancer stem cells exist in a variety of tumors.”
Advertisement
The idea that cancer cells possess the same properties as stem cells has been around for many years. Only recently have biologists developed techniques for identifying stem cells and their presence in tumors.
Cancer stem cells were first identified in certain types of leukemia in 1997 by John Dick and colleagues at the University of Toronto. They were harder to spot in solid tumors because biologists did not possess the means of recognizing the markers – characteristic proteins on the surface of a cell – that had been developed for a stem cell that makes red and white blood cells.
But in 2003, Michael Clarke, now of Stanford University, succeeded in finding cancer stem cells in breast tumors. Clarke showed that a vast majority of cells in a human breast tumor were incapable of further growth. Only a handful were able to seed new cancers, and these resembled stem cells in their ability to proliferate and generate mature cells.
In 2004, Peter Dirks of the University of Toronto identified similar stemlike cells in human brain tumors, and last year C. Parker Gibbs of the University of Florida reported seeing stemlike cells in bone cancer.
“It’s a very challenging population of cells to identify, but thus far in every cancer in which cells have been carefully screened they have been found,” said Gary Gilliland of Harvard University.
Process is unclear
Biologists are not yet sure how cancer stem cells are generated. It may be that the stem cells themselves suffer a mutation, or a change in their DNA instructions, that deranges the strict controls on their self-renewal. Or possibly their immediate progeny, known as progenitor cells, suffer some genetic damage after which, instead of developing into mature cells, they regain the power of self-renewal.
Self-renewal, the key property of stem cells, refers to their ability to divide unevenly. Other cells divide into two daughter cells, just as the parent cell does, but a stem cell can divide into a new stem cell and a progenitor cell. The progenitor cell loses the power of self-renewal but gains the ability to change or differentiate into the mature cell types of the tissue served by the stem cell.
After such a division, the number of stem cells in the tissue remains unchanged because one stem cell has been lost and one created. The stem cell population thus renews itself as it generates new cells.
The stem cells responsible for maintaining a tissue or an organ can presumably regulate their own numbers, perhaps by sensing through an exchange of chemicals when they have a quorum. Cancer stem cells differ in that they have lost control over their own population size.
The hypothesis explains several otherwise puzzling facts about cancer. Many of the body’s tissues that are most prone to cancer, like the blood, skin and lining of the gut, are composed of short-lived cells that suffer high wear and tear.
Yet cells are believed to become malignant only after a series of mutations has disabled their genetic control systems. How can a skin cell, which lives only a few weeks, survive long enough to accumulate the right sequence of mutations?
It is more plausible to suppose that mutations build up in the self-renewing population of stem cells that maintains the skin.
Pathologists have long recognized that tumors contain a variety of cells, including some that are characteristic of the tissue in which the cancer originates. But not all these cells are equally cancerous. If the cells from a tumor are injected back into a patient at a different site, as was done in a 1961 experiment that would now be considered unethical, more than a million cells must be used before a new tumor will form.
This supports the idea that only a tiny minority of the cells in a cancer have the ability to maintain it.
An amazingly successful anti-cancer drug is Gleevec, used to treat chronic myelogenous leukemia and three rarer cancers. Many patients who take Gleevec experience complete remission. But the drug does not cure the disease, which sometimes returns. It seems Gleevec is attacking not the cancer stem cells but the progenitor cells from which the cancerous white blood cells are generated.
Though many biologists believe that the cancer stem cell idea is interesting, not all think that it will lead to new therapies. In the view of Bert Vogelstein, a leading cancer researcher at Johns Hopkins University, everything depends on how much of a tumor consists of cancer stem cells.
Targeting tumors
If the proportion is large, as several experiments suggest, then current anti-cancer drugs must already be killing them, since they can kill up to 99% of the cells in a tumor. In which case, the idea is not so helpful.
“So the real attractiveness of the cancer stem cell hypothesis, in my view, is that if the 1 percent of cells that are left after successful chemotherapy are really cancer stem cells, then obviously that provides the rationale for different forms of therapy that target them,” Vogelstein said.
Gilliland, an advocate of the idea, acknowledged that 20% of cells in the solid tumors analyzed so far had stemlike properties. But with better markers, he said, it may turn out that a much smaller proportion are true cancer stem cells.
“If the growth of solid cancers were driven by cancer stem cells, it would have profound implications for cancer therapy,” Irving Weissman of Stanford has written. “Therapies that are more specifically directed against cancer stem cells might result in much more durable responses and even cures of metastatic tumors,” he and colleagues said.
Pharmaceutical companies are “waiting for more academic research before they take a clear view on how to proceed,” geneticist Weinberg said.
JS Online:Stem cells might be key to cancer
Posted by rob on under Uncategorized |
Research could shape new treatments
By NICHOLAS WADE
New York Times
Posted: Feb. 20, 2006
One day, perhaps in the distant future, stem cells may help repair diseased tissues. But there is a far more pressing reason to study them: Stem cells are the source of at least some, and perhaps all, cancers.
At the heart of every tumor, some researchers believe, lie a handful of aberrant stem cells that maintain the malignant tissue.
The idea, if right, could explain why tumors often regenerate even after being almost destroyed by anti-cancer drugs. It also points to a different strategy for developing anti-cancer drugs, suggesting they should be selected for lethality to cancer stem cells and not, as at present, for their ability to kill just any cells and shrink tumors.
“I think this is one of the most interesting developments in cancer research in the last five years,” said Robert Weinberg, a cancer geneticist at the Whitehead Institute in Cambridge, Mass. “I think more and more people are accepting it, and evidence is accumulating that cancer stem cells exist in a variety of tumors.”
The idea that cancer cells possess the same properties as stem cells has been around for many years. Only recently have biologists developed techniques for identifying stem cells and their presence in tumors.
Cancer stem cells were first identified in certain types of leukemia in 1997 by John Dick and colleagues at the University of Toronto. They were harder to spot in solid tumors because biologists did not possess the means of recognizing the markers – characteristic proteins on the surface of a cell – that had been developed for a stem cell that makes red and white blood cells.
But in 2003, Michael Clarke, now of Stanford University, succeeded in finding cancer stem cells in breast tumors. Clarke showed that a vast majority of cells in a human breast tumor were incapable of further growth. Only a handful were able to seed new cancers, and these resembled stem cells in their ability to proliferate and generate mature cells.
In 2004, Peter Dirks of the University of Toronto identified similar stemlike cells in human brain tumors, and last year C. Parker Gibbs of the University of Florida reported seeing stemlike cells in bone cancer.
“It’s a very challenging population of cells to identify, but thus far in every cancer in which cells have been carefully screened they have been found,” said Gary Gilliland of Harvard University.
Process is unclear
Biologists are not yet sure how cancer stem cells are generated. It may be that the stem cells themselves suffer a mutation, or a change in their DNA instructions, that deranges the strict controls on their self-renewal. Or possibly their immediate progeny, known as progenitor cells, suffer some genetic damage after which, instead of developing into mature cells, they regain the power of self-renewal.
Self-renewal, the key property of stem cells, refers to their ability to divide unevenly. Other cells divide into two daughter cells, just as the parent cell does, but a stem cell can divide into a new stem cell and a progenitor cell. The progenitor cell loses the power of self-renewal but gains the ability to change or differentiate into the mature cell types of the tissue served by the stem cell.
After such a division, the number of stem cells in the tissue remains unchanged because one stem cell has been lost and one created. The stem cell population thus renews itself as it generates new cells.
The stem cells responsible for maintaining a tissue or an organ can presumably regulate their own numbers, perhaps by sensing through an exchange of chemicals when they have a quorum. Cancer stem cells differ in that they have lost control over their own population size.
The hypothesis explains several otherwise puzzling facts about cancer. Many of the body’s tissues that are most prone to cancer, like the blood, skin and lining of the gut, are composed of short-lived cells that suffer high wear and tear.
Yet cells are believed to become malignant only after a series of mutations has disabled their genetic control systems. How can a skin cell, which lives only a few weeks, survive long enough to accumulate the right sequence of mutations?
It is more plausible to suppose that mutations build up in the self-renewing population of stem cells that maintains the skin.
Pathologists have long recognized that tumors contain a variety of cells, including some that are characteristic of the tissue in which the cancer originates. But not all these cells are equally cancerous. If the cells from a tumor are injected back into a patient at a different site, as was done in a 1961 experiment that would now be considered unethical, more than a million cells must be used before a new tumor will form.
This supports the idea that only a tiny minority of the cells in a cancer have the ability to maintain it.
An amazingly successful anti-cancer drug is Gleevec, used to treat chronic myelogenous leukemia and three rarer cancers. Many patients who take Gleevec experience complete remission. But the drug does not cure the disease, which sometimes returns. It seems Gleevec is attacking not the cancer stem cells but the progenitor cells from which the cancerous white blood cells are generated.
Though many biologists believe that the cancer stem cell idea is interesting, not all think that it will lead to new therapies. In the view of Bert Vogelstein, a leading cancer researcher at Johns Hopkins University, everything depends on how much of a tumor consists of cancer stem cells.
Targeting tumors
If the proportion is large, as several experiments suggest, then current anti-cancer drugs must already be killing them, since they can kill up to 99% of the cells in a tumor. In which case, the idea is not so helpful.
“So the real attractiveness of the cancer stem cell hypothesis, in my view, is that if the 1 percent of cells that are left after successful chemotherapy are really cancer stem cells, then obviously that provides the rationale for different forms of therapy that target them,” Vogelstein said.
Gilliland, an advocate of the idea, acknowledged that 20% of cells in the solid tumors analyzed so far had stemlike properties. But with better markers, he said, it may turn out that a much smaller proportion are true cancer stem cells.
“If the growth of solid cancers were driven by cancer stem cells, it would have profound implications for cancer therapy,” Irving Weissman of Stanford has written. “Therapies that are more specifically directed against cancer stem cells might result in much more durable responses and even cures of metastatic tumors,” he and colleagues said.
Pharmaceutical companies are “waiting for more academic research before they take a clear view on how to proceed,” geneticist Weinberg said.
JS Online:Stem cells might be key to cancer
Posted by rob on February 20, 2006 under Uncategorized |
Protein tyrosine phosphatase 1B (PTP-1B) is a ubiquitously expressed cytosolic phosphatase with the ability to dephosphorylate JAK2 and TYK2, and thereby down-regulate cytokine receptor signaling. Furthermore, PTP-1B levels are up-regulated in certain chronic myelogenous leukemia patients, which points to a potential role for PTP-1B in myeloid development. The results presented here show that the absence of PTP-1B affects murine myelopoiesis by modifying the ratio of monocytes to granulocytes in vivo. This bias toward monocytic development is at least in part due to a decreased threshold of response to CSF-1, because the PTP-1B -/- bone marrow presents no abnormalities at the granulocyte-monocyte progenitor level but produces significantly more monocytic colonies in the presence of CSF-1. This phenomenon is not due to an increase in receptor levels but rather to enhanced phosphorylation of the activation loop tyrosine. PTP-1B -/- cells display increased inflammatory activity in vitro and in vivo through the constitutive up-regulation of activation markers as well as increased sensitivity to endotoxin. Collectively, our data indicate that PTP-1B is an important modulator of myeloid differentiation and macrophage activation in vivo and provide a demonstration of a physiological role for PTP-1B in immune regulation.
Protein tyrosine phosphatase 1B negatively regulates macrophage development through CSF-1 signaling.
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Tumour formations arise as a consequence of alterations in the control of cell proliferation as well as with disorders in interactions between cells and their environment that result in invasion and metastasis. Recent advances in understanding the genetic basis of malignant diseases have been dominated by research in colorectal cancer. Genetic alterations of several proto-oncogenes and tumor-suppressor genes (e.g. APC/MCC, RAS, DCC, p53 mutations and/or allelic losses, hyperexpression of c-MYC and RB genes), as well as other genomic alterations, appear at characteristic stages of tumor development and are observed in most neoplasms. Generally, the normal cell has multiple independent mechanisms that regulate its growth and differentiation potential, and several separate events would, therefore, be needed to override these control mechanisms, as well as induce the other aspects of the transformed phenotype, like metastasis. These signals may be either positive or negative, and the acquisition of tumorigenicity results from genetic changes that affect these control points following a multistep mode. Statistics of the frequency of cancer incidence with age in humans indicate that for the genesis of e.g. lung carcinoma, five or six steps are required. Other types of cancers, such as leukemias and sarcomas, probably require quite a different number of rate-limiting changes. One of the best characterized tumours to provide a genetic model is colorectal tumorigenesis. Mutations implicated in breast cancer tumorigenicity are also studied and used as a genetic model in the literature worldwide. Finally, activation of c-abl in chronic myelogenous leukaemia (CML) and acute lymphoblastic leukaemia could also be presented as an example, which provides probably the strongest evidence for the role of proto-oncogenes in human malignancy process.
Genetic models of human cancer as a multistep process. Paradigm models of colorectal cancer, breast cancer, and chronic myelogenous and acute lymphoblastic leukaemia.
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Kinases are believed to play a crucial role in the expression and activation of inflammatory mediators in the airway, in T-cell function and airway remodelling. Important kinases such as Inhibitor of kappaB kinase (IKK)2, mitogen activated protein (MAP) kinases and phsopho-inositol (PI)3 kinase regulate inflammation either through activation of pro-inflammatory transcription factors such as activating protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB), which are activated in airway disease, or through regulation of mRNA half-life. Selective kinase inhibitors have been developed which reduce inflammation and some characteristics of disease in animal models. Targeting specific kinases that are overexpressed or over active in disease should allow for selective treatment of respiratory diseases. Interest in this area has intensified due to the success of the specific Abelson murine leukaemia viral oncogene (Abl) kinase inhibitor imatinib mesylate (Gleevec) in the treatment of chronic myelogenous leukaemia. Encouraging data from animal models and primary cells and early Phase I and II studies in other diseases suggest that inhibitors of p38 MAP kinase and IKK2 may prove to be useful novel therapies in the treatment of severe asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis and other inflammatory airway diseases.
Kinase inhibitors and airway inflammation.
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OBJECTIVE: To study the effect of co-expressing M-bcr/abl and m-bcr/abl fusion gene transcripts on the clinical features of the patients with chronic myelogenous leukemia (CML) at diagnosis. METHODS: m-bcr/abl fusion gene transcripts were detected by nested PCR. RESULTS: The percentage of the CML patients who co-expressed M-bcr/abl and m-bcr/abl was 51.4% at diagnosis. Comparison of the patients who co-expressed and those who expressed M-bcr/abl alone showed there was no difference in their hemoglobin concentrations, WBC counts, neutrophilic alkaline phosphatase (NAP) stains, Ph chromosomes and hepatosplenomegaly; however, significant difference in platelet count was seen. In the patients with b3a2 who co-expressed m-bcr/abl, an increased platelet count was noted, compared with that of patients with M-bcr/abl alone. But in patients with b2a2, the two groups showed no difference in all clinical features. Two patients had priapism, their m-bcr/abl being negative. CONCLUSIONS: CML patients who co-expressed b3a2 and m-bcr/abl showed a tendency to have an increased platelet count at diagnosis. Co-expressing m-bcr/abl has no the effect on the clinical features of CML patients with b2a2.
[Effect of co-expressing M-bcr/abl and m-bcr/abl fusion gene transcripts on the clinical features of patients with chronic myelogenous leukemia at diagnosis]
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The effects of a novel kind of nitrogen heterocycle compound, which was synthesized in our laboratory previously, on human chronic myelogenous leukemia K562 cells were investigated. The morphological changes were observed by Acridine orange (AO) staining. The screened results through DNA fragmentation and the Annexin V-FITC/PI staining assay showed that compound 8 blocked cell cycles at G(1) phase which led to apoptosis. The increase of caspase-3, 8, and 9 was detected, indicating that both of death-receptor and mitochondria-pathways were activated. Compound 8 induced a biphasic alteration in mitochondrial membrane potential of K562 cells. A dramatic elevation of Ca(2+) was also observed. In addition, a transient increase of ROS was also involved in the process. This study showed that compound 8 might be a potential chemopreventive agent for chronic myelogenous leukemia. It would guide our future work to synthesize more compounds derived from compound 8, which might have better effect, and to determine the target protein. Moreover, it might also provide a background mechanism for the introduction of this new type of promising therapeutic agent.
A novel kind of nitrogen heterocycle compound induces apoptosis of human chronic myelogenous leukemia K562 cells.
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BACKGROUND: Double pathology is uncommon. The diagnostic effort must be directed toward uncovering a disorder that can explain all the findings in a given patient. However, exceptions occur, notably in the sphere of infectious disorders. This is particularly true in the context of multiple infections in immunocompromised patients. CASE: Fine needle aspiration was performed on 2 lymph nodes in a 22-year-old male. Extramedullary hematopoiesis was seen in 1, while the other showed acellular necrosis with acid-fast bacilli. The hematologic workup revealed chronic myelogenous leukemia. CONCLUSION: Extramedullary hematopoiesis can be a cytologic clue to hematologic disorders. A search for an additional infectious disease may be in order.
Concurrent chronic myelogenous leukemia and turberculosis lymphadenitis: a case report.
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Rea D,
Legros L,
Raffoux E,
Thomas X,
Turlure P,
Maury S,
Dupriez B,
Pigneux A,
Choufi B,
Reman O,
Stéphane D,
Royer B,
Vigier M,
Ojeda-Uribe M,
Recher C,
Dombret H,
Huguet F,
Rousselot P
Imatinib combined with high-dose chemotherapy is now becoming the gold standard for treatment of Philadelphia chromosome-positive acute leukemias. However, in all studies imatinib dosage was tapered to 400-600 mg per day. We decided to initiate a clinical trial to evaluate an opposite strategy based on high-dose imatinib (800 mg per day) combined with a less intensive chemotherapeutic regimen (vincristine and dexamethasone), which we called the DIV induction regimen. Thirty-one patients (18 relapsing or refractory Ph+ acute lymphoblastic leukemias and 13 lymphoid blast crisis chronic myelogenous leukemias) were enrolled. Complete remission (CR) was obtained in 28 out of 30 assessable patients. The median bcr-abl/abl ratio after the induction course was 0.1%. Median time to neutrophil recovery was 21 days. Fungus infections were observed in six patients out of 31 and possibly related to dexamethasone. Neuropathy due to vincristine was noted in 14 cases. Nine out of 19 patients under 55 years received allogenic stem cell transplantation after a median time of 78 days post-CR. Patients older than 55 years experienced a 90% CR rate without additional toxicities, suggesting the DIV regimen may also be proposed as a front line therapy in older patients.Leukemia advance online publication, 26 January 2006; (2006) doi:10.1038/sj.leu.2404115.
High-dose imatinib mesylate combined with vincristine and dexamethasone (DIV regimen) as induction therapy in patients with resistant Philadelphia-positive acute lymphoblastic leukemia and lymphoid blast crisis of chronic myeloid leukemia.
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Yang H,
Eaves C,
de Lima M,
Lee MS,
Champlin RE,
McMannis JD,
Robinson SN,
Niu T,
Decker WK,
Xing D,
Ng J,
Li S,
Yao X,
Eaves AC,
Jones R,
Andersson BS,
Shpall EJ
Imatinib-refractory chronic myelogenous leukemia (CML) patients can experience long-term disease-free survival with myeloablative therapy and allogeneic hematopoietic cell transplantation; however, associated complications carry a significant risk of mortality. Transplantation of autologous hematopoietic cells has a reduced risk of complications, but residual tumor cells in the autograft may contribute to relapse. Development of methods for purging tumor cells that do not compromise the engraftment potential of the normal hematopoietic cells in the autograft has been a long-standing goal. Since primitive CML cells differentiate more rapidly in vitro than their normal counterparts and are also preferentially killed by mafosfamide and imatinib, we examined the purging effectiveness on CD34(+) CML cells using a strategy that combines a brief exposure to imatinib (0.5-1.0 muM for 72 h) and then mafosfamide (30-90 mug/ml for 30 min) followed by 2 weeks in culture with cytokines (100 ng/ml each of stem cell factor, granulocyte colony-stimulating factor and thrombopoietin). Treatment with 1.0 muM imatinib, 60 mug/ml mafosfamide and 14 days of culture with cytokines eliminated BCR-ABL(+) cells from chronic phase CML patient aphereses, while preserving normal progenitors. This novel purging strategy may offer a new approach to improving the effectiveness of autologous transplantation in imatinib-refractory CML patients.Bone Marrow Transplantation advance online publication, 23 January 2006; doi:10.1038/sj.bmt.1705284.
A novel triple purge strategy for eliminating chronic myelogenous leukemia (CML) cells from autografts.
