Investigators at St. Jude Children's Research Hospital have shown that when the cancer drug irinotecan is given in low doses for multiple days, it eliminates the need to delay treatment to perform costly genetic testing that determines if the patient is at risk for serious treatment side effects, such as neutropenia. Neutropenia is an abnormal reduction in the numbers of immune cells, called neutrophils; the disorder leaves individuals more vulnerable to infections.
The finding means that clinicians can begin treatment sooner and eliminate the cost of this specialized test, which determines if the child carries a variation in the gene UGT1A1 that is linked to this side effect of neutropenia. By giving the drug in small doses for two weeks instead of the standard single large dose once a month, children can begin treatment with irinotecan immediately. Irinotecan is used to treat childhood solid tumors such as neuroblastoma, sarcomas and kidney tumors.
A report on this study is in the June 20 issue of the “Journal of Clinical Oncology.”
UGT1A1 makes an enzyme that modifies the activated form of irinotecan, a molecule called SN-38, so the body can easily remove it. Variations of this enzyme, especially one called UGT1A1*28, do not work as well and allow SN-38 to remain in the body at high levels for an extended period of time, causing side effects.
Like many genes, UGT1A1 has a series of DNA building blocks called thymidine and adenine (TA) repeating several times just in front of the gene itself. This area, called the promoter region, acts as an “on” switch that triggers the reading of the gene. The normal UGT1A1 has six copies of TA in front of it, while UGT1A1*28 has seven.
Previous studies had shown that when adults who carry two copies of the UGT1A1*28 gene variation received a single high dose of irinotecan, they suffered severe diarrhea or neutropenia, said Clinton Stewart, Pharm.D., associate member of the St. Jude Department of Pharmaceutical Sciences and the report’s first author.
“The U.S. Food and Drug Administration requires the irinotecan package labeling to indicate that patients with UGT1A1*28 are at increased risk for neutropenia and that clinicians should consider using a reduced dosage for these individuals,” Stewart said. “Based on this warning, we wanted to determine if children with the UGT1A1*28 gene variation were likely to suffer the same toxicity even if they received irinotecan in 10 small doses over two weeks instead of one large dose.”
The St. Jude team conducted a retrospective study of 74 children who had received this low-dose treatment for any of a variety of solid tumors. A total of 27 children had both copies of the normal gene UGT1A1 with six copies of TA in the promoter region; 36 had one normal and one UGT1A1*28 gene with seven copies of TA; and nine had two copies of UGT1A1*28.
The researchers found no association between UGT1A1*28 and either diarrhea or neutropenia—even if the patient had two copies of this gene when irinotecan was given at the reduced dose. Therefore, the researchers concluded that it was not useful to test patients to determine if they had UGT1A1*28.
“This is a negative finding in the sense that the UGT1A1*28 variation does not seem to predict toxic responses in patients treated with low-dose irinotecan,” said Lisa McGregor, M.D., Ph.D., assistant member of the St. Jude Department of Oncology and the report’s senior author. “But it should help clinicians design effective and safe irinotecan treatments for individual children.”
Summer Freeman | EurekAlert!
Organ-on-a-chip mimics heart's biomechanical properties
23.02.2017 | Vanderbilt University
Researchers identify cause of hereditary skeletal muscle disorder
22.02.2017 | Klinikum der Universität München
In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport
Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...
The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.
The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...
Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...
Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".
Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...
13.02.2017 | Event News
10.02.2017 | Event News
09.02.2017 | Event News
24.02.2017 | Life Sciences
24.02.2017 | Life Sciences
24.02.2017 | Trade Fair News