Effects of o,p’-DDE, a Mitotane Metabolite, in an Adrenocortical Carcinoma Cell Line

Bach, Camila; Corso, Christopher D.; Veiga, Alan de Almeida; Paraizo, Mariana M; Souza, Lauro Mera de

doi:10.3390/ph15121486

Cited by 3 publications

(1 citation statement)

References 48 publications

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“…These transformations are mediated by the CYP450 family, an active enzyme system that is highly expressed in the adrenal gland. It has been demonstrated that DDE is an active metabolite of mitotane, although it is present at low plasma concentrations, while it is still debated whether DDA is active or not [10,11].…”

Section: Introductionmentioning

confidence: 99%

Albumin/Mitotane Interaction Affects Drug Activity in Adrenocortical Carcinoma Cells: Smoke and Mirrors on Mitotane Effect with Possible Implications for Patients’ Management

Schiavon,

Saba,

Catucci

et al. 2023

IJMS

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Background: Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). Although it has been used for many years, its mechanism of action remains elusive. H295R cells are, in ACC, an essential tool to evaluate drug mechanisms, although they often lead to conflicting results. Methods: Using different in vitro biomolecular technologies and biochemical/biophysical experiments, we evaluated how the presence of “confounding factors” in culture media and patient sera could reduce the pharmacological effect of mitotane and its metabolites. Results: We discovered that albumin, the most abundant protein in the blood, was able to bind mitotane. This interaction altered the effect of the drug by blocking its biological activity. This blocking effect was independent of the albumin source or methodology used and altered the assessment of drug sensitivity of the cell lines. Conclusions: In conclusion, we have for the first time demonstrated that albumin does not only act as an inert drug carrier when mitotane or its metabolites are present. Indeed, our experiments clearly indicated that both albumin and human serum were able to suppress the pharmacological effect of mitotane in vitro. These experiments could represent a first step towards the individualization of mitotane treatment in this rare tumor.

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Section: Introductionmentioning

confidence: 99%

Albumin/Mitotane Interaction Affects Drug Activity in Adrenocortical Carcinoma Cells: Smoke and Mirrors on Mitotane Effect with Possible Implications for Patients’ Management

Schiavon,

Saba,

Catucci

et al. 2023

IJMS

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Two-dimensional chromatography for enantiomeric analysis of mitotane and its metabolite o,p′-DDA in patients with adrenocortical carcinoma indicates enantioselective metabolism

Stadler,

de Almeida Veiga,

Rita Corso

et al. 2023

Bioorganic Chemistry

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International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects

Riedmeier,

Antonini,

Brandalise

et al. 2024

European Journal of Endocrinology

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Objective Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects. Methods A Delphi method with three rounds of questionnaires within the pACC expert consortium of the international network groups ENSAT-PACT and ICPACT was used to create 21 final consensus statements. Results We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stage III and IV and with incomplete resection/tumor spillage. For stage II patients mitotane is not generally indicated.The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14-20 mg/L Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2 to 4 weeks), along with evaluation and assessment of laboratory values are required. Conclusion Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.

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Effects of o,p’-DDE, a Mitotane Metabolite, in an Adrenocortical Carcinoma Cell Line

Cited by 3 publications

References 48 publications

Albumin/Mitotane Interaction Affects Drug Activity in Adrenocortical Carcinoma Cells: Smoke and Mirrors on Mitotane Effect with Possible Implications for Patients’ Management

Albumin/Mitotane Interaction Affects Drug Activity in Adrenocortical Carcinoma Cells: Smoke and Mirrors on Mitotane Effect with Possible Implications for Patients’ Management

Two-dimensional chromatography for enantiomeric analysis of mitotane and its metabolite o,p′-DDA in patients with adrenocortical carcinoma indicates enantioselective metabolism

International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects

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