[ad_1]
Despite being studied for decades, the cisplatin chemotherapy drug reveals new aspects of its functioning. Researchers at the Winship Cancer Institute of Emory University have identified an enzyme responsible for tumor resistance and cancer cell lines in cisplatin, as well as an experimental drug targeting this enzyme.
The results were published on July 19 in Cancer Cell .
Cisplatin is a DNA destructive agent used in the standard treatment of cancers of the lung, head and neck, ovarian and testicles. It has a simple structure, grabbing DNA with its metal arms (platinum) to form crosslinks. It was known as "cis-flatten" because of its side effects inducing nausea. The experimental drug, lestaurtinib, has already been tested in clinical studies in combination with other chemotherapeutic drugs, which means that it could easily go into testing against tumors displaying resistance to cisplatin.
Sumin Kang, PhD and colleagues of Winship enzymes whose activity was necessary for cancer cells to resist treatment with cisplatin. They have chosen kinases, enzymes that often control certain aspects of cell growth and have many existing drugs that target them. The researchers found that, in combination with a sub-lethal amount of cisplatin, "knock-down" MAST1 kinase activity kills a cell. "We have tested all types of drug resistance mechanisms," says Kang, an badistant professor of hematology and medical oncology at the Emory University School of Medicine and a recipient of Scholar Scholar Scholarship at Winship. "It seems like it's" post-target. "It does not mean that cells get rid of the drug faster, and it does not work with other agents that damage DNA, so it does not happen. Is not related to an improved repair. "
Survival enzymes, cRaf and MEK1, with which cisplatin interferes. Cisplatin was known to damage DNA and release reactive oxygen species into the cell, but the interaction between cisplatin and survival enzymes had not been observed before, Kang said. Levels of MAST1 appear to explain cisplatin resistance in a study of cancer cell lines and primary human tumor samples
. The next step was to look for compounds that could inhibit MAST1. The Kang team has found one in letraurtinib, a kinase inhibitor that has already been the subject of clinical trials for several types of cancer, such as acute myeloid leukemia. This was a surprise because pretaurin inhibited another type of kinase (tyrosine kinase) than MAST1.
"This opens up several possibilities, such as leturinib, and other inhibitors," says Kang. "We think that targeting MAST1 would be better than MEK1 because the elimination of MAST1 does not have much of a toxic effect on the cells by itself."
Potentially, such a combination could reduce the dose of cisplatin several times, reducing side
In animal models with implanted tumors, cisplatin could be badociated with letauraurib against several types of cancer cells: the cells squamous head and neck, lung cancer, ovarian and cervical carcinomas
. : "The targeted treatment with MAST1 would be more beneficial for patients with advanced cancers or for those receiving platinum-based therapy, but in part due to the induction of MAST1 during treatment. Future pharmacokinetic studies and toxicity and clinical trials are warranted … "
The first author of the article is Associate Research Scientist Lingtao Jin, Ph.D. Co-authors include Sagar Lonial, MD, chairman of the Department of 39, Hematology and Medical Oncology and Chief Medical Officer of Winship, Dong Moon Shin, MD, Winship Medical Oncologist and Professor of Hematology and Medical Oncology, and Nabil Saba, MD, Director of The Oncology Program of the Winship Head and Neck and Professor of Hematology and Medical Oncology
The research was supported by the National Cancer Institute (R01CA175316, R01CA207768 ), the Ministry of Defense (W81XW H-17-1-0186) (IRG-17-181-04) and the Georgia Cancer Coalition
SOURCE: Emory University
[ad_2]
Source link
