title: Prolonged oxaliplatin exposure alters intracellular calcium signaling: a new mechanism to explain oxaliplatin-associated peripheral neuropathy.
abstract: BACKGROUND
  Oxaliplatin is a platinum-based cytotoxic agent commonly used to treat colorectal cancers. Despite its effectiveness, oxaliplatin administration is associated with the development of cold-induced peripheral neuropathy. This potentially permanent side effect is provoked by cold exposure and can range from mild and self limited to severe and debilitating. Even with tumor shrinkage, these painful side effects can force dose reduction or discontinuation of treatment. Neither the mechanism of action of oxaliplatin nor that of cold-induced neuropathy is understood. Paclitaxel, an entirely different chemotherapeutic agent used to treat a variety of malignancies, also is associated with the development of peripheral neuropathy. Unlike oxaliplatin, neurotoxicity arising from paclitaxel treatment was previously found to have profound effects on intracellular calcium signaling.
  
  
  RESULTS
  In this study we examined the effects of oxaliplatin on calcium signaling pathways and found that acute exposure of either a neuroblastoma cell line or primary neurons with therapeutic concentrations of oxaliplatin had no effect on intracellular calcium signaling. We also found that cellular temperature sensors (transient receptor potential [TRP] channels) were also not activated by oxaliplatin. Interestingly, prolonged exposure of oxaliplatin sensitized cells to subsequent stimuli and enhanced the magnitude of intracellular calcium responses.
  
  
  CONCLUSIONS
  Taken together, our results suggest that acute oxaliplatin exposure will not induce abnormal calcium signaling but oxaliplatin-primed cells do exhibit enhanced sensitivity. These findings provide new insight to the mechanism behind oxaliplatin-induced neuropathy.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066, USA.
authors.forename: Christin
authors.initials: C
authors.lastname: Schulze
authors.forename: Margit
authors.initials: M
authors.lastname: McGowan
authors.forename: Sven-Eric
authors.initials: SE
authors.lastname: Jordt
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Ehrlich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D020013:Calcium Signaling / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin