A therapeutic technique to scale back the unwanted side effects of chemotherapy | press room

Convergent effects of cisplatin and KW6002 on DNA double-strand breaks in lung tumor cells.  Blue corresponds to cell nuclei and red to a protein that marks DNA damage.

Convergent effects of cisplatin and KW6002 on DNA double-strand breaks in lung tumor cells. Blue corresponds to cell nuclei and red to a protein that marks DNA damage. © Dewaeles et al.

Cisplatin is a chemotherapy drug indicated to fight tumors in many types of cancer. However, it is associated with significant side effects, most notably renal toxicity, which can lead to acute renal failure. In addition, patients treated with cisplatin often report significant neuropathic pain as well. Scientists from Inserm, the University and University Hospital of Lille, the CNRS and the Institut Pasteur de Lille in the CANTHER laboratories[1] and Lille Neuroscience & Cognition, in collaboration with researchers at Michigan State University (USA), have identified a drug that could be a game changer for patients. This molecule, called istradefylline, which is already approved for treating Parkinson’s disease, could not only reduce the harmful effects of chemotherapy but also improve its anti-tumor properties. These results must now be consolidated in a clinical study. The study was published in The Journal of Clinical Investigation.

Cisplatin is a chemotherapy drug used to treat various types of cancer, including lung, ovarian, and testicular cancer. With proven anti-tumor efficacy, this therapy is also associated with side effects, including severe pain (peripheral neuropathy) and kidney damage, which in one third of cases can go as far as acute kidney failure. Currently there is no specific solution to limit these problems, which affect many patients exposed to cisplatin.

In order to improve their management, the development of new therapeutic strategies is therefore a major research area for many scientists.

This is the case of the teams led by Christelle Cauffiez, David Blum and Geoffroy Laumet from CANTHER Laboratories (Inserm/ /CNRS/University of Lille/CHU of Lille), Lille Neuroscience & Cognition (Inserm/University of Lille/CHU). of Lille ) and the Michigan State University Department of Physiology who have identified a molecule capable of reducing the side effects of cisplatin while maintaining or even enhancing its anti-tumor properties.

A drug for Parkinson’s disease

Scientists became interested in a drug called “Istradefylline,” which is already approved in the US and Japan to treat Parkinson’s disease. This drug works by blocking receptors on the surface of our cells called adenosine receptors.

David Blum’s team, which deals with neurodegenerative pathologies, had already established that these receptors are found to be increased in the brains of patients in a pathological context and that this phenomenon is involved in the development of these diseases. However, Christelle Cauffiez’s team also observed a similar increase in adenosine receptors in the kidneys when the body was exposed to cisplatin.

Therefore, in the face of this observation, the scientists decided to jointly test the effects of istradefylline to see if blocking these receptors allows reducing the harmful effects of cisplatin.

Results must be confirmed in a clinical study

Their experiments, conducted using animal and cell models, effectively indicated the beneficial role of istradefylline. In fact, in mice exposed to this chemotherapy, the molecule works by reducing not only the damage to kidney cells but also the pain caused by cisplatin.

In addition, cisplatin’s ability to reduce tumor growth was increased in animals given istradefylline, which was later confirmed in cell models.

Before considering the generalization of this therapeutic approach for cancer patients, these results must first be consolidated through the organization of a rigorous clinical trial. Still, the fact that istradefylline is already being used in humans to treat another pathology is already an interesting prospect.

“In fact, we already have a lot of clinical trial data showing that this molecule is safe. If there is a need to conduct a clinical trial to test efficacy in reducing the side effects of chemotherapy, the possibility of therapeutic repositioning is a promising prospect to improve patient management in the short term.” say the researchers.

[1] Laboratory for Heterogeneity, Plasticity and Resistance to Cancer Therapy (CANTHER)

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