Late Breaking News
- Categorized in: July 2009 Issue
Stem-Like Immune Cells Destroy Tumors in Mice
A new approach to stimulating immune cells enhances their anticancer activity, resulting in a powerful anti-tumor response in mice, according to a study by researchers at the National Cancer Institute. The work appeared online June 14, 2009, in Nature Medicine.
Researchers found that a subset of immune cells, T lymphocytes called CD8+ memory stem cells, were capable of mediating strong anti-tumor immune response. These potent cells were generated in the laboratory by stimulating anti-tumor T cells in the presence of drugs designed to mimic an important signaling pathway called Wnt, which describes a complex network of proteins whose interactions are essential during development and stem cell maintenance. Under the influence of Wnt, T lymphocytes acquired stem cell-like properties of multipotency and self-renewal; that is, they generated differentiating daughter cells while regenerating themselves when transferred back to mice from the lab. These stem cell-like qualities enabled tiny numbers of T cells (about 40,000 cells) to trigger the destruction of large melanoma tumors (containing about one billion malignant cells).
This therapy, in which mice received CD8+ T memory stem cells together with a tumor vaccine and an immune system stimulant known as interleukin 2, improved the survival of treated mice compared with similar treatments using other types of memory T cells.
Current clinical immunotherapies based on the transfer of tumor-specific T cells generated and expanded in the laboratory rely on the use of large numbers of tumor-specific T cells and have had beneficial but sometimes limited success. If confirmed in humans, the use of tumor-reactive CD8+ memory stem cells could reduce the numbers of tumor-specific T cells needed for successful immunotherapy, thus making this type of therapy easier to develop, so that more patients could benefit.
These findings mark the latest advance in the field of cancer immunotherapy using tumor-specific T cells, which researchers believe is moving from proof-of-concept to a promising treatment for patients with metastatic cancer.
Gene Variant Linked to Chemotherapy Resistance in Breast Cancer Patients
Researchers have found links between an individual’s genetics and their response to treatment with chemotherapy. The findings, by researchers at the National Cancer Institute and their colleagues, show how a genetic variant located in the SOD2 gene may affect how a person responds to the chemotherapy drug cyclophosphamide. Cyclophosphamide is used in the treatment of breast and other cancers.
The SOD2 gene produces a key protein that protects cells from damage by molecules known as reactive oxygen species, or free radicals. Reactive oxygen species are produced by normal cellular processes and the action of some chemotherapy drugs. The findings represent the first preliminary evidence pointing toward a mechanism and a potential biomarker for cyclophosphamide resistance in breast cancer patients. The study appeared online June 9, 2009, in Clinical Cancer Research.
Most genes in human cells are present in two copies—one inherited from the mother and the other from the father. These gene copies can vary from one another. Some variations in genes play an important role in how a gene is expressed or how its protein product functions.
The variant identified by the researchers in the SOD2 gene affects both the structure and the function of the encoded protein, an enzyme known as manganese superoxide dismutase (MnSOD), and it affects the ability of MnSOD to reach its proper location in the cell and its activity level. MnSOD normally functions inside cellular compartments known as mitochondria, and helps protect cells from damage caused by reactive oxygen species formed during cellular metabolism. Excessive levels of reactive oxygen species can be toxic to cells. Indeed, some anticancer drugs depend on increased production of reactive oxygen species to kill cancer cells. Furthermore, some studies have indicated that because MnSOD neutralizes reactive oxygen species, it can modify the effects of chemotherapy drugs. For example, in laboratory and animal models, increased activity of MnSOD protects cells against the toxic effects of doxorubicin, which is a widely used anticancer drug.
In the new study, the research team investigated whether the variation affected survival in two separate groups of women with breast cancer: 248 women in the United States and 340 women in Norway. Some of the women received chemotherapy, and some did not receive chemotherapy. The team first analyzed DNA from the women to determine which types of the SOD2 gene they had. The researchers found that, among patients who received chemotherapy, those who had one form had decreased survival, and those with another form had the poorest survival. In contrast, the genotype of SOD2 did not affect survival among those who did not receive chemotherapy.
Next, the team looked at the relationship between SOD2 genotype and the type of chemotherapy the women received. The data were analyzed according to which of three types of commonly used chemotherapy drugs were administered: doxorubicin, 5-fluorouracil, or cyclophosphamide. Both doxorubicin and cyclophosphamide generate reactive oxygen species in cancer cells during treatment. The researchers determined that the presence of a particular variant was associated with decreased survival of patients treated with chemotherapy regimens that contained any of the three drugs. However, the most significant effects were found with the drug cyclophosphamide. Women with a distinct variant form of SOD2 and who received cyclophosphamide-containing chemotherapy had the poorest survival.
The research team says more work is necessary to confirm these findings and to examine the precise mechanism by which a genotype influences the response of cancer cells to cyclophosphamide. The team plans to examine the influence of several variations on the resistance to other chemotherapies.
Common Autism Drug No Better Than Placebo, Study Shows
Citalopram, a medication commonly prescribed to children with autism spectrum disorders, was no more effective than a placebo at reducing repetitive behaviors, according to researchers funded by the National Institute of Mental Health. The study was published in the June 2009 issue of Archives of General Psychiatry.
The researchers say their findings do not support using citalopram to treat repetitive behaviors in children with ASD. Also, the greater frequency of side effects from this particular medication compared to placebo illustrates the importance of placebo-controlled trials in evaluating medications currently prescribed to this population.
Researchers in the Studies to Advance Autism Research and Treatment (STAART) network, funded by five NIH institutes, conducted a six-site, randomized controlled trial comparing the effectiveness and safety of using citalopram (Celexa) versus placebo to treat repetitive behaviors in children with ASD. The study included 149 participants, ages 5–17, who had autism, Asperger disorder, or pervasive developmental disorder-not otherwise specified (PDD-NOS).
After12weeksoftreatment,roughlyoneoutofthreechildreninbothgroups—32.9%ofthosetreatedwithcitalopramand34.2%thosetreated with placebo—showed fewer or less severe repetitive symptoms. “Adverse symptoms were common in both groups, probably reflecting common childhood ailments as well as the changing nature of symptoms associated with ASD,” noted Bryan King, MD, director of child and adolescent psychiatry at Seattle Children’s Hospital and lead author on the study, in a statement. However, reports of increased energy, impulsiveness, decreased concentration, hyperactivity, diarrhea, insomnia, and dry skin were more common in the citalopram group.
According to the researchers, the study results may challenge the underlying premise that repetitive behaviors in children with ASD are similar to repetitive and inflexible behaviors in OCD.
Aspirin and Anti-Clotting Drug Reduce Risk of Dialysis Access Failure
For the first time, a combination of aspirin and the anti-platelet drug dipyridamole, has been shown to significantly reduce blockages and extend the useful life of new artery-vein access grafts used for hemodialysis, according to a study by the Dialysis Access Consortium. The study, supported by the National Institute of Diabetes and Digestive and Kidney Diseases, was published in the May 21, 2009, New England Journal of Medicine.
Artery-vein access grafts, called arteriovenous grafts, fail most often due to narrowing of blood vessels at the graft site and subsequent clotting, which block the flow of blood. A blocked graft cannot be used for dialysis, and is a major cause of worsening health in dialysis patients. The DAC trial found that the combination treatment decreased the rate of loss of primary unassisted graft patency — the useful life of a graft before it becomes blocked the first time — by 18%, and the rate of developing significant stenosis by 28%, compared to placebo. Previous smaller clinical trials of anti-clotting therapies failed to show that these drugs improve AV graft patency, or that they could be used safely in dialysis patients.
A total of 649 participants with new AV grafts were recruited for the trial at 13 clinical sites in the United States, and were randomly assigned to treatment with dipyridamole plus aspirin or a placebo. The trial took place over a period of 5 years. NIDDK established the multicenter Dialysis Access Consortium in September 2000 to design and implement a series of randomized, controlled, clinical trials over a 5-year period to identify effective therapies to reduce the rate of graft and fistula failure in dialysis patients.
Injectable Form of Ibuprofen Approved for Use in Hospitals
The Food and Drug Administration last month approved Caldolor, the first injectable dosage form of the common pain medication ibuprofen, to treat pain and fever for patients unable to take oral medications.
Caldolor, manufactured by Cumberland Pharmaceuticals, Inc., Nashville, Tenn., will be available for hospital use only. It is approved to be administered in 400 mg to 800 mg doses, over 30 minutes, every 6 hours for acute pain. To treat fever, the drug is approved in a 400 mg dose administered over 30 minutes, followed by 400 mg every 4 to 6 hours, or 100-200 mg every 4 hours, as necessary.
In a clinical trial of 319 women who had undergone an elective abdominal hysterectomy, patients were less likely to request morphine for pain on an as-needed basis when administered Caldolor.
According to the product’s labeling, Caldolor should be used with caution in patients with congestive heart failure, kidney impairment, at-risk for blood clots, and those with a prior history of ulcers or gastrointestinal bleeding. When used in such patients, attention to using the lowest effective dose for the shortest time period is important to reduce the risk of serious adverse events. The drug has also been associated with high blood pressure, serious skin reactions, and serious allergic reactions.
The most common adverse reactions reported in the controlled clinical trials were nausea, flatulence, vomiting, and headache.