Abstract

BackgroundChemotherapy-induced neuropathy is the principle dose limiting factor requiring discontinuation of many chemotherapeutic agents, including cisplatin and oxaliplatin. About 30 to 40% of patients receiving chemotherapy develop pain and sensory changes. Given that poly (ADP-ribose) polymerase (PARP) inhibition has been shown to provide neuroprotection, the current study was developed to test whether the novel PARP inhibitor compound 4a (analog of ABT-888) would attenuate pain in cisplatin and oxaliplatin-induced neuropathy in mice.ResultsAn established chemotherapy-induced painful neuropathy model of two weekly cycles of 10 intraperitoneal (i.p.) injections separated by 5 days rest was used to examine the therapeutic potential of the PARP inhibitor compound 4a. Behavioral testing using von Frey, paw radiant heat, cold plate, and exploratory behaviors were taken at baseline, and followed by testing at 3, 6, and 8 weeks from the beginning of drug treatment.ConclusionCisplatin-treated mice developed heat hyperalgesia and mechanical allodynia while oxaliplatin-treated mice exhibited cold hyperalgesia and mechanical allodynia. Co-administration of 50 mg/kg or 25 mg/kg compound 4a with platinum regimen, attenuated cisplatin-induced heat hyperalgesia and mechanical allodynia in a dose dependent manner. Similarly, co-administration of 50 mg/kg compound 4a attenuated oxaliplatin-induced cold hyperalgesia and mechanical allodynia. These data indicate that administration of a novel PARP inhibitor may have important applications as a therapeutic agent for human chemotherapy-induced painful neuropathy.

Highlights

  • Peripheral neuropathy remains the principle dose limiting toxicity for many chemotherapeutic agents, including plant alkaloids, taxanes, and platinum-based compounds [1]

  • To examine the effects of poly (ADP-ribose) polymerase (PARP) inhibitor compound 4a on reduction of body weight in the chemotherapy-induced neuropathy model, mean time course body weight was evaluated in mice after platinum treatment with or without PARP inhibitor

  • After two cycles of dosing, 50 m/kg compound 4a or 25 mg/kg compound 4a with cisplatin combination showed no significant difference in mean body weight compared to cisplatin alone (Fig. 2A)

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Summary

Introduction

Peripheral neuropathy remains the principle dose limiting toxicity for many chemotherapeutic agents, including plant alkaloids, taxanes, and platinum-based compounds (e.g., cisplatin, oxaliplatin, and carboplatin) [1]. For example, induces axonal neuropathy, characterized by a glove-and stocking distribution of sensory changes including dysesthesia, paraesthesia, and pain, at a cumulative dose .400–500 mg/m2. These symptoms frequently develop several weeks to months after initiation of chemotherapy and improve after treatment ends [7]. Chemotherapy-induced neuropathy is the principle dose limiting factor requiring discontinuation of many chemotherapeutic agents, including cisplatin and oxaliplatin. Given that poly (ADP-ribose) polymerase (PARP) inhibition has been shown to provide neuroprotection, the current study was developed to test whether the novel PARP inhibitor compound 4a (analog of ABT888) would attenuate pain in cisplatin and oxaliplatin-induced neuropathy in mice

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