Format

Send to

Choose Destination
Clin Colorectal Cancer. 2011 Jun;10(2):126-33. doi: 10.1016/j.clcc.2011.03.010. Epub 2011 Apr 22.

Prolonged oxaliplatin exposure alters intracellular calcium signaling: a new mechanism to explain oxaliplatin-associated peripheral neuropathy.

Author information

1
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066, USA.

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.

METHODS AND 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.

PMID:
21859566
PMCID:
PMC3388801
DOI:
10.1016/j.clcc.2011.03.010
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center