Adenosine Receptor Antagonist, Istradefylline, Reduces Chemotherapy Side Effects in Mice Such as Cisplatin-Induced Kidney Toxicity and Painful Neuropathy

Presenter(s)

Hariharan Ramakrishnan

Abstract or Description

    Cisplatin is an incredibly powerful chemotherapy drug used to treat a variety of cancers. However, its side-effects such as kidney toxicity and painful neuropathy may result in dose reduction or termination of treatment increasing patient mortality. Physicians must closely monitor patient’s kidney function during chemotherapy, due to high risk of kidney failure, and the patient’s sensitivity, due to severe pain from peripheral neuropathy. Therefore, there is an urgent medical need for novel therapeutics that limit cisplatin’s side-effects. Adenosine receptors are involved in several kidney diseases and neuropathic pain pathophysiology. We hypothesize that blocking adenosine receptors (AR) using Istradefylline, an FDA-approved AR antagonist, will alleviate kidney toxicity and pain from cisplatin. To test this, we treated mice with cisplatin (3 mg/kg for 5 days) and found that they developed pain hypersensitivity, measured through the von Frey method, and kidney toxicity, measured by high gene-expression of kidney injury marker (KIM-1). Since pain and kidney toxicity are often associated with inflammation, we also collected tissue samples from the spinal cord, peripheral nervous ganglion, and kidney to measure the gene-expression of inflammatory cytokines through quantitative PCR. Mice treated with cisplatin had higher levels of expression of these inflammatory mediators in all tissues compared to mice treated with saline (control). We found administration of Istradefylline reduces both the pain hypersensitivity and kidney toxicity induced by cisplatin as well as the associated inflammation. Since Istradefylline is already approved by the FDA for the treatment of Parkinson’s disease, it can be quickly clinically applied to cancer therapy.

Mentor

Geoffroy Laumet, Jaewon Sim