Chemotherapy-induced peripheral neuropathy—part 2: focus on the prevention of oxaliplatin-induced neurotoxicity

Abstract

Background Chemotherapy-induced peripheral neuropathy (CIPN) is regarded as one of the most common dose-limiting adverse effects of several chemotherapeutic agents, such as platinum derivatives (oxaliplatin and cisplatin), taxanes, vinca alkaloids and bortezomib. CIPN affects more than 60% of patients receiving anticancer therapy and although it is a nonfatal condition, it significantly worsens patients' quality of life. The number of analgesic drugs used to relieve pain symptoms in CIPN is very limited and their efficacy in CIPN is significantly lower than that observed in other neuropathic pain types. Importantly, there are currently no recommended options for effective prevention of CIPN, and strong evidence for the utility and clinical efficacy of some previously tested preventive therapies is still limited. Methods The present article is the second one in the two-part series of review articles focused on CIPN. It summarizes the most recent advances in the field of studies on CIPN caused by oxaliplatin, the third-generation platinum-based antitumor drug used to treat colorectal cancer. Pharmacological properties of oxaliplatin, genetic, molecular and clinical features of oxaliplatin-induced neuropathy are discussed. Results Available therapies, as well as results from clinical trials assessing drug candidates for the prevention of oxaliplatininduced neuropathy are summarized. Conclusion Emerging novel chemical structures-potential future preventative pharmacotherapies for CIPN caused by oxaliplatin are reported.

Synthesis, anticonvulsant, and antinociceptive activity of new 3‐(3‐methyl‐2,5‐dioxo‐3‐phenylpyrrolidin‐1‐yl)propanamides and 3‐phenyl‐butanamides

“…[ 32,34 ] In contrast to this, chronic peripheral neuropathy after oxaliplatin treatment is mainly due to a permanent distal sensory loss, the death of sensory neurons, and nerve cell necrosis, which all result from binding of oxaliplatin to mitochondrial DNA. [ 29,35 ] As shown in Figure 3, compound 6 reduced cold allodynia mainly in the acute phase of neuropathy, which suggests its potential action through VGSCs, VGCCs, or other types of ion channels. Compound 7 was not effective in the cold plate test, and although the in vitro part of the present study showed its effect on VGSCs and VGCCs, this activity of compound 7 was not strong enough to provide effective attenuation of cold‐exacerbated pain.…”

“…Neurotoxicity of oxaliplatin appears in two distinct forms, that is, acute and chronic. [ 29 ] We aimed to test compounds 6 and 7 during both these phases of CIPN to elucidate potential mechanisms underlying in vivo activity of these compounds. Acute neuropathy caused by oxaliplatin results from a transient impairment of ion channels and nerve hyperexcitability due to VGSC activation [ 30–32 ] and VGCC activation.…”

Wide-Range Measurement of Thermal Preference—A Novel Method for Detecting Analgesics Reducing Thermally-Evoked Pain in Mice

“…As other platinum-based compounds (e.g., cisplatin and carboplatin), oxaliplatin impairs the proliferation of tumor cells by forming deoxyribonucleic acid-platinum adducts and this activity results in cancer cell death. In humans, oxaliplatin is used in combination with folinic acid and 5-fluorouracil (FOLFOX therapy) or with folinic acid, 5-fluorouracil and irinotecan (FOLFOXIRI therapy) as the first-line or adjuvant treatment of colorectal cancer [ 1 ].…”

“…Of note, oxalate that is formed from oxaliplatin is responsible for the observed cold-induced hypersensitivity in patients on oxaliplatin therapy. Oxalate acts as a calcium chelator, which stimulates the removal of extracellular calcium ions, and this leads to the increased sodium conductance, neuronal depolarization and hyperexcitability [ 1 ].…”

“…In contrast to tactile allodynia, which can be effectively attenuated by analgesic adjuvants (e.g., pregabalin), hypersensitivity to cold stimuli is regarded as the main and still not addressed clinical issue in patients on oxaliplatin therapy. This clinical entity is pharmacoresistant to available analgesics and according to the guidelines of the American Society of Clinical Oncology (ASCO) only duloxetine, an analgesic adjuvant is moderately recommended for the prevention of oxaliplatin-induced cold-exacerbated pain [ 1 ]. Considering this, novel treatment options and novel analgesics for the alleviation of cold allodynia/hyperalgesia are strongly needed.…”