Mercier Cedric, Dupuis Charlotte, Blesius Aurore, Fanciullino Raphaelle, Yang Chen Guang, Padovani Laetitia, Giacometti Sarah, Frances Nicolas, Iliadis Athanassios, Duffaud Florence, Ciccolini Joseph
Medical Oncology Unit, La Timone University Hospital, Marseille, France.
Cancer Chemother Pharmacol. 2009 May;63(6):1177-80. doi: 10.1007/s00280-008-0889-1. Epub 2008 Dec 24.
We report here the case of a 19-year-old female patient who suffered from extremely severe toxicities (G4 mucitis, fever, diarrhea, alteration of general state) while undergoing low-dose capecitabine treatment for her metastatic corticosurrenaloma. The severe toxicities stopped as soon as treatment was suspended. Interestingly, this patient was not deficient in DPD, a pharmacogenetic syndrome usually associated with increased risk of developing severe/lethal toxicities in patients undergoing fluoropyrimidine therapy, and she had been treated previously with 5-FU with a good tolerance. We then hypothesized that cytidine deaminase (CDA) extensive phenotype could be responsible for the severe toxicities observed with capecitabine. CDA is affected by genetic polymorphism, with subsequent acquisition of either deficient or extensive metabolizer profile. Phenotypic investigations confirmed that CDA activity in this patient was +180% higher than the ones usually recorded in the general population. This strongly suggests that the extensive activation of triple-prodrug capecitabine could have occurred in this patient, resulting in overexposure to 5-FU and its cytotoxic metabolites eventually. This case report suggest for the first time that severe toxicities with a capecitabine-containing protocol could be, at least in part, linked with an extensive-CDA syndrome. The case reported here suggests therefore that besides DPD, screening for CDA activity could be of interest to ensure a better safety in the handling of oral capecitabine at the bedside.
我们在此报告一例19岁女性患者的病例，该患者在接受低剂量卡培他滨治疗转移性肾上腺皮质瘤时出现了极其严重的毒性反应（4级粘膜炎、发热、腹泻、全身状况改变）。治疗一暂停，严重毒性反应就停止了。有趣的是，该患者并不缺乏二氢嘧啶脱氢酶（DPD），这是一种通常与接受氟嘧啶治疗的患者发生严重/致命毒性反应风险增加相关的药物遗传学综合征，并且她之前接受过5-氟尿嘧啶（5-FU）治疗，耐受性良好。然后我们推测胞苷脱氨酶（CDA）广泛代谢型可能是导致卡培他滨所致严重毒性反应的原因。CDA受基因多态性影响，随后会出现代谢缺陷型或广泛代谢型。表型研究证实，该患者的CDA活性比一般人群中通常记录的活性高180%。这强烈表明该患者可能发生了三前体药物卡培他滨的广泛活化，最终导致5-FU及其细胞毒性代谢产物暴露过量。本病例报告首次表明，含卡培他滨方案的严重毒性反应至少部分可能与CDA广泛代谢综合征有关。因此，此处报告的病例表明，除了检测DPD外，检测CDA活性可能有助于在床边使用口服卡培他滨时确保更好的安全性。
