Association of mitotane with chylomicrons and serum lipoproteins: practical implications for treatment of adrenocortical carcinoma.

Abstract

OBJECTIVE:

Oral mitotane (o,p'-DDD) is a cornerstone of medical treatment for adrenocortical carcinoma (ACC).

AIM:

Serum mitotane concentrations >14  mg/l are targeted for improved efficacy but not achieved in about half of patients. Here we aimed at a better understanding of intestinal absorption and lipoprotein association of mitotane and metabolites o,p'-dichlorodiphenylacetic acid (o,p'-DDA) and o,p'-dichlorodiphenyldichloroethane (o,p'-DDE).

DESIGN:

Lipoproteins were isolated by ultracentrifugation from the chyle of a 29-year-old patient and serum from additional 14 ACC patients treated with mitotane. HPLC was applied for quantification of mitotane and metabolites. We assessed NCI-H295 cell viability, cortisol production, and expression of endoplasmic reticulum (ER) stress marker genes to study the functional consequences of mitotane binding to lipoproteins.

RESULTS:

Chyle of the index patient contained 197  mg/ml mitotane, 53  mg/ml o,p'-DDA, and 51  mg/l o,p'-DDE. Of the total mitotane in serum, lipoprotein fractions contained 21.7±21.4% (VLDL), 1.9±0.8% (IDL), 8.9±5.5% (LDL1), 18.9±9.6% (LDL2), 10.1±4.0% (LDL3), and 26.3±13.0% (HDL2). Only 12.3±5.5% were in the lipoprotein-depleted fraction.

DISCUSSION:

Mitotane content of lipoproteins directly correlated with their triglyceride and cholesterol content. O,p'-DDE was similarly distributed, but 87.9±4.2% of o,p'-DDA found in the HDL2 and lipoprotein-depleted fractions. Binding of mitotane to human lipoproteins blunted its anti-proliferative and anti-hormonal effects on NCI-H295 cells and reduced ER stress marker gene expression.

CONCLUSION:

Mitotane absorption involves chylomicron binding. High concentrations of o,p'-DDA and o,p'-DDE in chyle suggest intestinal mitotane metabolism. In serum, the majority of mitotane is bound to lipoproteins. In vitro, lipoprotein binding inhibits activity of mitotane suggesting that lipoprotein-free mitotane is the therapeutically active fraction.

• Authors: Matthias Kroiss, Dietmar Plonné, Sabine Kendl, Diana Schirmer, Cristina L Ronchi, Andreas Schirbel, Martina Zink, Constantin Lapa, Hartwig Klinker, Martin Fassnacht, Werner Heinz, Silviu Sbiera
• Journal: European journal of endocrinology (Eur J Endocrinol) Vol. 174 Issue 3 Pg. 343-53 (Mar 2016) ISSN: 1479-683X [Electronic] England
• PMID: 26671975 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 European Society of Endocrinology.

Chemical References

• Antineoplastic Agents, Hormonal
• Chylomicrons
• Lipoproteins
• Lipoproteins, HDL2
• Lipoproteins, IDL
• Lipoproteins, LDL
• Lipoproteins, VLDL
• 2,2-(2-chlorophenyl-4'-chlorophenyl)acetic acid
• Mitotane
• 2,2-(2-chlorophenyl-4'-chlorophenyl)-1,1-dichloroethene

Topics

• Adrenal Cortex Neoplasms (drug therapy)
• Adrenocortical Carcinoma (drug therapy)
• Adult
• Aged
• Antineoplastic Agents, Hormonal (metabolism, pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromatography, High Pressure Liquid
• Chyle (chemistry)
• Chylomicrons (metabolism)
• Cohort Studies
• Endoplasmic Reticulum Stress (drug effects)
• Female
• Gastrointestinal Absorption
• Humans
• Lipoproteins (metabolism, pharmacology)
• Lipoproteins, HDL2 (metabolism)
• Lipoproteins, IDL (metabolism)
• Lipoproteins, LDL (metabolism)
• Lipoproteins, VLDL (metabolism)
• Male
• Middle Aged
• Mitotane (analogs & derivatives, metabolism, pharmacology, therapeutic use)