Abstract
Oxaliplatin, an anti-cancer chemotherapeutic agent used for the treatment of colorectal cancer, commonly causes gastrointestinal side-effects such as constipation, diarrhoea, nausea, and vomiting. Damage to enteric neurons may underlie some of these gastrointestinal side-effects, as the enteric nervous system (ENS) controls functions of the bowel. In this study, neuronal loss and changes to the structure and immunoreactivity of myenteric neuronal nitric oxide synthase (nNOS) neurons were examined in colonic segments from mice following exposure to oxaliplatin ex vivo and following repeated intraperitoneal injections of oxaliplatin over 3 weeks in vivo, using immunohistochemistry and confocal microscopy. Significant morphological alterations and increases in the proportion of NOS-immunoreactive (IR) neurons were associated with both short-term oxaliplatin exposure and long-term oxaliplatin administration, confirming that oxaliplatin causes changes to the myenteric neurons. Long-term oxaliplatin administration induced substantial neuronal loss that was correlated with a reduction in both the frequency and propagation speed of colonic migrating motor complexes (CMMCs) in vitro. Similar changes probably produce some symptoms experienced by patients undergoing oxaliplatin treatment.
Highlights
Oxaliplatin, a third-generation platinum drug, has become one of the first-line therapies used in the treatment of metastatic colorectal cancer (de Gramont et al, 2000; Petrioli et al, 2008)
After 24 h in culture, the high dose oxaliplatin group displayed a higher proportion of nitric oxide synthase (NOS)-IR myenteric neurons than controls (Figure 1A)
This study is the first to examine the effects of oxaliplatin on the myenteric neurons in a mouse model of chemotherapy
Summary
Oxaliplatin, a third-generation platinum drug, has become one of the first-line therapies used in the treatment of metastatic colorectal cancer (de Gramont et al, 2000; Petrioli et al, 2008). Administered in combination with 5-fluorouracil and leucovorin, oxaliplatin has been shown to improve response rates and survival of patients (André et al, 2004), and has anti-tumor activity against some cancer cell lines resistant to first-generation (cisplatin) and second-generation (carboplatin) platinum drugs (Machover et al, 1996; Louvet et al, 2002; Raymond et al, 2002). Oxaliplatin preferentially binds to guanine clusters to mainly form intrastrand crosslinks (Woynarowski et al, 1998; Hector et al, 2001; Fuertes et al, 2003; Kweekel et al, 2005; Wang and Lippard, 2005). The platinum-DNA adducts formed are believed to inhibit DNA replication and transcription and to induce apoptosis or necrosis in cancer cells and rapidly dividing cell lines (Fuertes et al, 2003; Kweekel et al, 2005)
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