ECE2011 Poster Presentations Endocrine tumours and neoplasia (37 abstracts)
Distribution of mitotane and its two metabolites in liproprotein fractions of patients with adrenocortical carcinoma
Y Cazaubon 1, , S Broutin 2 , A Seck 1, , H Remy 3, , F Lemare 3 , J M Bidart 4 , C Chougnet 5 , S Leboulleux 5 , M Schlumberger 5 , E Baudin 5 & A Paci 1,
1UMR 8203 Institut Gustave Roussy, Villejuif, France; 2Pharmacology and Drug Analysis Department, Villejuif, France; 3Clinical Pharmacy Department, Villejuif, France; 4Biology and Biopathology Department, Villejuif, France; 5Nuclear Medecine and Endocrine Cancerology Department, Villejuif, France.
Introduction: Adrenocortical carcinoma (ACC) is a rare tumor of the adrenals with poor prognosis (survival rate for metastatic patients <15% at 5 years). Mitotane (o,p′-DDD) is the main therapeutic option with up to 66% objective response rates in patients with serum levels between 14 and 20 mg/l. Its two main metabolites are o,p′-DDA and o,p′-DDE which plasma levels are not correlated to therapeutic response. Mitotane is a lipophilic drug that accumulates in lipoproteins and induces hypercholesterolemia by activation of HMGCoA reductase. Looking for predictive/prognostic markers of response we assessed the distribution of o,p′-DDD and its metabolites in lipoprotein fractions of ACC patients.
Materials and methods: Levels of o,p′-DDD, o,p′-DDA and o,p′-DDE were measured using HPLC-UV method after liquid-liquid extraction with p,p′-DDE as internal standard. Lipoprotein fractions from plasma of ACC patients treated with mitotane were obtained by differential ultracentrifugation process.
Results: We developed and validated an HPLC-UV method. The extraction yields of o,p′-DDD, o,p′-DDA and o,p′-DDE are 75, 73 and 38% respectively. This method is linear, precise, accurate and no matrix effect was observed (<2%). The method of separation of lipoproteins by differential ultracentrifugation allowed us isolating VLDL, LDL and the mixture HDL-proteins. Analyses in a few plasma patients showed a major distribution of o,p′-DDA in HDL (99%) while o p′-DDD and o,p′-DDE were mainly measured in HDL (>70%), partially in LDL (12–25%) and barely in VLDL (<5%).
Conclusion: This work allowed us to define conditions for the study of o,p′-DDD, o,p′-DDA and o,p′-DDE distribution in the different lipoprotein fractions. The preliminary results showed a different distribution profile for o,p′-DDA. The perspectives of this study are multiple: evaluation of lipoprotein distribution over time in a large cohort of patients; dyslipoprotidemia impact; relationship between o,p′-DDD, o,p′-DDA and o,p′-DDE lipoprotein plasma levels and therapeutic response.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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