2-2-(2-chlorophenyl-4--chlorophenyl)-1-1-dichloroethene and Adrenal-Cortex-Neoplasms

The adrenolytic agent mitotane (o,p'-DDD or 1,1-(o,p'-dichlorodiphenyl)-2,2-dichoroethane) is believed to be metabolically activated, resulting in the generation of reactive intermediates or the formation of o,p'-DDA. A new high-performance liquid chromatographic (HPLC) method for measurement of mitotane and two of its metabolites, o,p'-DDA (1,1-(o,p'-dichlorodiphenyl) acetic acid) and o,p'-DDE (1,1-(o,p'-dichlorodiphenyl)-2,2 dichloroethene), in plasma has been developed. Sample preparation involves precipitation of plasma proteins with acetone before chromatographic separation under isocratic conditions on a silica-based diphenyl column. Mitotane and metabolites are quantified by ultraviolet detection at 218 nm. Recoveries for the three compounds range between 99% and 110%, with between-day and within-day coefficients of variation <6% within the therapeutic range. Limits of detection are 0.5 microM and the assay is linear up to at least 800 microM for o,p'-DDA and 100 microM for mitotane and o,p'-DDE. The method has been evaluated using samples from three patients on mitotane therapy, revealing o,p'-DDA levels in plasma 3 to 10 times higher than the levels of the parent compound.

Topics: Adrenal Cortex Neoplasms; Adrenergic Agents; Adult; Aged; Antineoplastic Agents, Hormonal; Chromatography, High Pressure Liquid; Drug Stability; Female; Humans; Linear Models; Male; Middle Aged; Mitotane

Mitotane is the reference drug for the adrenocortical carcinoma treatment; its pharmacological activity seems to depend on drug transformation in two active metabolites: o,p'-DDE (dichlorodiphenylethene) and o,p'-DDA (dichlorodiphenylacetate). Mitotane and metabolites are lipophilic agents; thus, they tend to accumulate into adipose tissues (white and brown), which change their prevalence seasonally. Aim of the work was to evaluate mitotane and metabolites plasma levels variation over the year, in adrenocortical cancer patients treated with Lysodren. We enrolled a group of 86 adrenocortical carcinoma diagnosed patients, who underwent radical surgery and started mitotane as adjuvant treatment. For drug and metabolites plasma level (from samples collected ~12 h after the dose administration of mitotane, just before the subsequent administration) determination, a validated chromatographic method was used.. Results showed an evidence of a seasonal trend for the three substance (o,p'-DDD, o,p'-DDE and o,p'-DDA) plasma levels, in terms of acrophases and lower values. Furthermore, it came out that male patients need a higher significant mitotane drug dose than female patients to reach mitotane therapeutic window.. In conclusion, this is the first study assessing a mitotane plasma level variation over the year, but further studies in larger cohorts are required.

Topics: Adipose Tissue; Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adult; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Chromatography, High Pressure Liquid; Female; Humans; Male; Middle Aged; Mitotane; Seasons; Sex Factors; Time Factors; Young Adult

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

Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adult; Aged; Antineoplastic Agents, Hormonal; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Chyle; Chylomicrons; Cohort Studies; Endoplasmic Reticulum Stress; Female; Gastrointestinal Absorption; Humans; Lipoproteins; Lipoproteins, HDL2; Lipoproteins, IDL; Lipoproteins, LDL; Lipoproteins, VLDL; Male; Middle Aged; Mitotane

In patients with adrenocortical carcinoma (ACC) mitotane activity has been suggested to depend on plasma levels 14 mg/liter or greater and metabolite formation.. The study was performed to confirm the correlation of the currently used mitotane (o,p'DDD) threshold of 14 mg/liter with tumor response and to evaluate the additional value of 1,1-(o,p'-dichlorodiphenyl) acetic acid (o,p'DDA) and o,p'DDE (1,1-(o,p'-dichlorodiphenyl)-2,2 dichloroethene) levels for predicting tumor response.. Plasma samples collected within 3 months of best response from 91 patients on mitotane therapy for advanced ACC were analyzed retrospectively. O,p'DDD and metabolites were assessed and related to tumor response and survival. Receiver operating characteristic curves were used. Sensitivity and specificity were calculated for different cutoff levels of o,p'DDD and metabolites.. Objective tumor response was observed in 19% of patients. Median o,p'DDD level was higher in responders (P = 0.03). More responders were found among patients achieving o,p'DDD levels 14 mg/liter or greater (P = 0.02). Univariate and multivariate analysis showed significantly longer survival for patients with o,p'DDD levels 14 mg/liter or greater (hazard ratio 0.52, P = 0.04, hazard ratio 0.46, P = 0.03). An o,p'DDD cutoff value of 14 mg/liter was associated with a sensitivity of 65% and specificity 69%. An o,p'DDD level 20 mg/liter or greater or 14 mg/liter or greater combined with o,p'DDA level 92 mg/liter or greater was associated with a specificity of 90 and 92%, respectively.. Our data confirm the value of o,p'DDD plasma monitoring as well as targeting the 14 mg/liter cutoff level in the therapeutic management of ACC patients. Furthermore, our results suggest additional benefit of higher levels of o,p'DDD and combined measurement of o,p'DDD and o,p'DDA.

Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Female; Humans; Male; Middle Aged; Mitotane; Predictive Value of Tests; Retrospective Studies; Sensitivity and Specificity