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!
Nanoparticles as a Solution against Antibiotic Resistance?
15.12.2017 | Friedrich-Schiller-Universität Jena
Plasmonic biosensors enable development of new easy-to-use health tests
14.12.2017 | Aalto University
DNA molecules that follow specific instructions could offer more precise molecular control of synthetic chemical systems, a discovery that opens the door for engineers to create molecular machines with new and complex behaviors.
Researchers have created chemical amplifiers and a chemical oscillator using a systematic method that has the potential to embed sophisticated circuit...
MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.
Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...
Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...
Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.
To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...
The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.
Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...
11.12.2017 | Event News
08.12.2017 | Event News
07.12.2017 | Event News
15.12.2017 | Power and Electrical Engineering
15.12.2017 | Materials Sciences
15.12.2017 | Life Sciences