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Massimo Terzolo - One of the best experts on this subject based on the ideXlab platform.
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Recovery of Adrenal Insufficiency Is Frequent After Adjuvant Mitotane Therapy in Patients with Adrenocortical Carcinoma.
Cancers, 2020Co-Authors: Jonathan Poirier, Massimo Terzolo, Soraya Puglisi, Anna Calabrese, Nadia Gagnon, Nada El Ghorayeb, André Lacroix, Isabelle BourdeauAbstract:Mitotane is a steroidogenesis inhibitor and adrenolytic drug used for treatment of adrenocortical cancer (ACC). Mitotane therapy causes adrenal insufficiency requiring glucocorticoid replacement in all patients. However, it is unclear whether chronic therapy with Mitotane induces complete destruction of zona fasciculata and whether hypothalamic-pituitary-adrenal (HPA) axis can recover after treatment cessation. Our objective was to assess the HPA axis recovery in a cohort of patients after cessation of adjuvant Mitotane therapy for ACC. We retrospectively reviewed patient files with stage I-II-III ACC in two referral centers in Canada and Italy. Data on demographics, tumor characteristics, hormonal profile, and HPA axis were collected. Data from 23 patients with pathologically proven ACC treated with adjuvant Mitotane for a minimum of two years were analyzed. Eight patients were males and 15 were females and the median age was 41 years old (range 18 to 73). After Mitotane cessation, 18/23 (78.3%) patients achieved a complete HPA axis recovery while 3/23 (13.0%) were unable to tolerate glucocorticoid withdrawal despite having normal hormonal test values and 2/23 (8.7%) never achieved recovery. The mean time interval between Mitotane cessation and HPA axis recovery was 2.7 years. A high proportion of patients achieved HPA axis recovery following cessation of Mitotane adjuvant therapy. However, complete recovery was often delayed up to 2.5 years and regular assessment of the hormonal profile is required.
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New perspectives for Mitotane treatment of adrenocortical carcinoma.
Best practice & research. Clinical endocrinology & metabolism, 2020Co-Authors: Soraya Puglisi, Giuseppe Reimondo, Paola Perotti, Anna Pia, Anna Calabrese, Vittoria Basile, Massimo TerzoloAbstract:Adrenocortical carcinoma (ACC) is an aggressive cancer characterized by poor survival. Apart from radical surgery, there is a limited range of therapeutic options and Mitotane remains the cornerstone of medical treatment of ACC in either adjuvant or palliative settings. The aim of adjuvant Mitotane therapy is to reduce the risk of ACC recurrence following surgical removal of the tumor. Use of Mitotane in an adjuvant setting is off-label, but the recent guidelines endorsed by the European Society of Endocrinology (ESE) and the European Network for the Study of Adrenal Tumors (ENSAT) recommend it in ACC patients at high risk of recurrence. The palliative use of Mitotane for treatment of advanced ACC aims at controlling tumor progression and, when present, hormone secretion. In this clinical setting, Mitotane is used in association with chemotherapy to treat the more aggressive forms, while Mitotane monotherapy is reserved for less progressive ACC. Many years after its introduction in clinical practice, there are still uncertainties surrounding the use of this old drug and the derived benefits. Moreover, physicians who use Mitotane should recognize and manage the systemic effects of the drug that need a complex supporting therapy.
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Mitotane: new facts for an old drug
Current Opinion in Endocrine and Metabolic Research, 2019Co-Authors: Anna Calabrese, Soraya Puglisi, Paola Perotti, Vittoria Basile, Massimo TerzoloAbstract:Abstract Adrenocortical carcinoma (ACC) is an aggressive cancer with poor long-term survival. Apart from radical surgery, there is a reduced range of therapeutic possibilities, and Mitotane remains the cornerstone of the treatment in the adjuvant and palliative setting. Although many decades after its introduction in clinical practice, there are still many uncertainties surrounding the applied use and the actual benefit of this old drug. Recent adrenocortical carcinoma guidelines suggest adjuvant Mitotane for patients at high risk of recurrence and chemotherapy plus Mitotane for metastatic disease; moreover, the use of Mitotane monotherapy has been proposed in a subset of patients. When using Mitotane, physicians have to consider and manage its potential toxicity and endocrine effects that need a complex supporting therapy.
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CYP11B1 has no role in Mitotane action and metabolism in adrenocortical carcinoma cells.
PloS one, 2018Co-Authors: Antonina Germano, Silvia De Francia, Marco Volante, Ida Rapa, Alfredo Berruti, Laura Saba, Paola Perotti, Massimo TerzoloAbstract:Mitotane is the reference drug for adrenocortical carcinoma (ACC) and the metabolic activation of the drug is considered as essential for its activity. The aim of this study was to assess the role of CYP11B1 on Mitotane action and metabolism in H295R ACC cells to understand whether this enzyme may influence Mitotane action. The simultaneous incubation with Mitotane and metyrapone, an adrenolytic molecule targeting 11-beta-hydroxylase, did not influence Mitotane-mediated cytotoxic effect and metabolism in H295R ACC cells. CYP11B1 silencing confirmed the lack of a significant metyrapone effect on Mitotane action. The present findings do not support the view that CYP11B1 catalyzes a crucial step in the metabolic activation of Mitotane and that CYP11B1 confers the adrenal specificity to Mitotane.
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Circannual variation of Mitotane and its metabolites plasma levels in patients with adrenocortical carcinoma
The Journal of pharmacy and pharmacology, 2017Co-Authors: Jessica Cusato, Silvia De Francia, Sarah Allegra, Simona Carrella, Elisa Pirro, Francesca Piccione, Francesca De Martino, Anna Maria Ferrero, Fulvia Daffara, Massimo TerzoloAbstract:Objectives 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® for at least 6 months. Methods 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. Key findings 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. Conclusions In conclusion, this is the first study assessing a Mitotane plasma level variation over the year, but further studies in larger cohorts are required.
Maria Chiara Zatelli - One of the best experts on this subject based on the ideXlab platform.
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effects of Mitotane on the hypothalamic pituitary adrenal axis in patients with adrenocortical carcinoma
European Journal of Endocrinology, 2017Co-Authors: Giuseppe Reimondo, Silvia De Francia, Marco Volante, Barbara Zaggia, Laura Saba, Paola Perotti, Maria Chiara Zatelli, Soraya Puglisi, Vittoria Basile, Salvatore CannavòAbstract:Objective Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency. Recent studies in vitro have also documented a direct inhibitory effect of Mitotane at the pituitary level. The present study was aimed to assess the hypothalamic-pituitary-adrenal axis in patients with ACC receiving Mitotane. Design and methods We prospectively enrolled 16 patients on adjuvant treatment with Mitotane after radical surgical resection of ACC, who underwent standard hormone evaluation and h-CRH stimulation. A group of 10 patients with primary adrenal insufficiency (PAI) served as controls for the CRH test. Results We demonstrated a close correlation between cortisol-binding globulin (CBG) and plasma Mitotane levels, and a non-significant trend between Mitotane dose and either serum or salivary cortisol in ACC patients. We did not find any correlation between the dose of cortisone acetate and either ACTH or cortisol levels. ACTH levels were significantly higher in patients with PAI than that in patients with ACC, both in baseline conditions (88.99 (11.04-275.00) vs 24.53 (6.16-121.88) pmol/L, P = 0.031) and following CRH (158.40 (34.32-275.00) vs 67.43 (8.8-179.52) pmol/L P = 0.016). Conclusions The observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that Mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels. In conclusion, the present study shows that Mitotane affects the HPA axis at multiple levels and no single biomarker may be used for the assessment of adrenal insufficiency.
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Effects of Mitotane on the hypothalamic–pituitary–adrenal axis in patients with adrenocortical carcinoma
European journal of endocrinology, 2017Co-Authors: Giuseppe Reimondo, Silvia De Francia, Marco Volante, Barbara Zaggia, Laura Saba, Paola Perotti, Maria Chiara Zatelli, Soraya Puglisi, Vittoria Basile, Salvatore CannavòAbstract:Objective Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency. Recent studies in vitro have also documented a direct inhibitory effect of Mitotane at the pituitary level. The present study was aimed to assess the hypothalamic-pituitary-adrenal axis in patients with ACC receiving Mitotane. Design and methods We prospectively enrolled 16 patients on adjuvant treatment with Mitotane after radical surgical resection of ACC, who underwent standard hormone evaluation and h-CRH stimulation. A group of 10 patients with primary adrenal insufficiency (PAI) served as controls for the CRH test. Results We demonstrated a close correlation between cortisol-binding globulin (CBG) and plasma Mitotane levels, and a non-significant trend between Mitotane dose and either serum or salivary cortisol in ACC patients. We did not find any correlation between the dose of cortisone acetate and either ACTH or cortisol levels. ACTH levels were significantly higher in patients with PAI than that in patients with ACC, both in baseline conditions (88.99 (11.04-275.00) vs 24.53 (6.16-121.88) pmol/L, P = 0.031) and following CRH (158.40 (34.32-275.00) vs 67.43 (8.8-179.52) pmol/L P = 0.016). Conclusions The observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that Mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels. In conclusion, the present study shows that Mitotane affects the HPA axis at multiple levels and no single biomarker may be used for the assessment of adrenal insufficiency.
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Mitotane enhances doxorubicin cytotoxic activity by inhibiting P-gp in human adrenocortical carcinoma cells.
Endocrine, 2014Co-Authors: Teresa Gagliano, Erica Gentilin, Ettore C. Degli Uberti, Katiuscia Benfini, Carmelina Di Pasquale, Martina Tassinari, Simona Falletta, Carlo V. Feo, Federico Tagliati, Maria Chiara ZatelliAbstract:Mitotane is currently employed as adjuvant therapy as well as in the medical treatment of adrenocortical carcinoma (ACC), alone or in combination with chemotherapeutic agents. It was previously demonstrated that Mitotane potentiates chemotherapeutic drugs cytotoxicity in cancer cells displaying chemoresistance due to P-glycoprotein (P-gp), an efflux pump involved in cancer multidrug resistance. The majority of ACC expresses high levels of P-gp and is highly chemoresistent. The aim of our study was to explore in vitro whether Mitotane, at concentrations lower than those currently reached in vivo, may sensitize ACC cells to the cytotoxic effects of doxorubicin and whether this effect is due to a direct action on P-gp. NCI-H295 and SW13 cell lines as well as 4 adrenocortical neoplasia primary cultures were treated with Mitotane and doxorubicin, and cell viability was measured by MTT assay. P-gp activity was measured by calcein and P-gp-Glo assays. P-gp expression was evaluated by Western blot. We found that very low Mitotane concentrations sensitize ACC cells to the cytotoxic effects of doxorubicin, depending on P-gp expression. In addition, Mitotane directly inhibits P-gp detoxifying function, allowing doxorubicin cytotoxic activity. These data provide the basis for the greater efficacy of combination therapy (Mitotane plus chemotherapeutic drugs) on ACC patients. Shedding light on Mitotane mechanisms of action could result in an improved design of drug therapy for patients with ACC.
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Inhibitory effects of Mitotane on viability and secretory activity in mouse gonadotroph cell lines
Reproductive toxicology (Elmsford N.Y.), 2014Co-Authors: Erica Gentilin, Daniela Molè, Teresa Gagliano, Mariella Minoia, Maria Rosaria Ambrosio, Ettore C. Degli Uberti, Maria Chiara ZatelliAbstract:Mitotane represents the mainstay medical treatment for metastatic, inoperable or recurrent adrenocortical carcinoma. Besides the well-known adverse events, Mitotane therapy is associated also with endocrinological effects, including sexual and reproductive dysfunction. The majority of male patients undergoing adjuvant Mitotane therapy show a picture of hypogonadism, characterized by low free testosterone and high sex hormone binding globulin levels and unmodified LH concentrations. Since Mitotane has been shown to have direct pituitary effects, we investigated whether Mitotane may influence both cell viability and function of gonadotroph cells in the settings of two pituitary cell lines. We found that Mitotane reduces cell viability, induces apoptosis, modifies cell cycle phase distribution and secretion of gonadotroph cells. The present data strengthen previous evidence showing a direct Mitotane effect at pituitary level and represent a possible explanation of the lack of LH increase following decrease in free testosterone in patients undergoing adjuvant Mitotane therapy.
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Inhibitory effects of Mitotane on viability and secretory activity in mouse gonadotroph cell lines
'Elsevier BV', 2014Co-Authors: Erica Gentilin, Daniela Molè, Teresa Gagliano, Mariella Minoia, Maria Rosaria Ambrosio, Ettore Degli C Uberti, Maria Chiara ZatelliAbstract:Medical therapy for Cushing's disease (CD) is currently based on agents mainly targeting adrenocortical function. Lately, pituitary-directed drugs have been developed, with limited efficacy. Mitotane, a potent adrenolytic drug, has been recently investigated for the treatment of CD, but the direct pituitary effects have not been clarified so far. The aim of our study was to investigate whether Mitotane may affect corticotroph function and cell survival in the mouse pituitary cell line AtT20/D16v-F2 and in the primary cultures of human ACTH-secreting pituitary adenomas, as an in vitro model of pituitary corticotrophs. We found that in the AtT20/D16v-F2 cell line and in primary cultures, Mitotane reduces cell viability by inducing caspase-mediated apoptosis and reduces ACTH secretion. In the AtT20/D16v-F2 cell line, Mitotane reduces Pomc expression and blocks the stimulatory effects of corticotropin-releasing hormone on cell viability, ACTH secretion, and Pomc expression. These effects were apparent at Mitotane doses greater than those usually necessary for reducing cortisol secretion in Cushing's syndrome, but still in the therapeutic window for adrenocortical carcinoma treatment. In conclusion, our results demonstrate that Mitotane affects cell viability and function of human and mouse ACTH-secreting pituitary adenoma cells. These data indicate that Mitotane could have direct pituitary effects on corticotroph cells
Fulvia Daffara - One of the best experts on this subject based on the ideXlab platform.
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Circannual variation of Mitotane and its metabolites plasma levels in patients with adrenocortical carcinoma
The Journal of pharmacy and pharmacology, 2017Co-Authors: Jessica Cusato, Silvia De Francia, Sarah Allegra, Simona Carrella, Elisa Pirro, Francesca Piccione, Francesca De Martino, Anna Maria Ferrero, Fulvia Daffara, Massimo TerzoloAbstract:Objectives 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® for at least 6 months. Methods 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. Key findings 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. Conclusions In conclusion, this is the first study assessing a Mitotane plasma level variation over the year, but further studies in larger cohorts are required.
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Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection
European journal of endocrinology, 2013Co-Authors: Massimo Terzolo, Fulvia Daffara, Matthias Kroiss, A E Baudin, A Ardito, S. Leboulleux, P Perotti, R A Feelders, J H Devries, B ZaggiaAbstract:Context: Mitotane plasma concentrations R14 mg/l have been shown to predict tumor response and better survival in patients with advanced adrenocortical carcinoma (ACC). A correlation between Mitotane concentrations and patient outcome has not been demonstrated in an adjuvant setting. Objective: To compare recurrence-free survival (RFS) in patients who reached and maintained Mitotane concentrations R14 mg/l vs patients who did not. Design and setting: Retrospective analysis at six referral European centers. Patients: Patients with ACC who were radically resected between 1995 and 2009 and were treated adjuvantly with Mitotane targeting concentrations of 14–20 mg/l. Main outcome measures: RFS (primary) and overall survival (secondary). Results: Of the 122 patients included, 63 patients (52%) reached and maintained during a median follow-up of 36 months the target Mitotane concentrations (group 1) and 59 patients (48%) did not (group 2). ACC recurrence was observed in 22 patients of group 1 (35%) and 36 patients in group 2 (61%). In multivariable analysis, the maintenance of target Mitotane concentrations was associated with a significantly prolonged RFS (hazard ratio (HR) of recurrence: 0.418, 0.22–0.79; PZ0.007), while the risk of death was not significantly altered (HR: 0.59, 0.26–1.34; PZ0.20). Grades 3–4 toxicity was observed in 11 patients (9%) and was managed with temporary Mitotane discontinuation. None of the patients discontinued Mitotane definitively for toxicity. Conclusions: Mitotane concentrations R14 mg/l predict response to adjuvant treatment being associated with a prolonged RFS. A monitored adjuvant Mitotane treatment may benefit patients after radical removal of ACC.
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Ribonucleotide Reductase Large Subunit (RRM1) Gene Expression May Predict Efficacy of Adjuvant Mitotane in Adrenocortical Cancer
Clinical cancer research : an official journal of the American Association for Cancer Research, 2012Co-Authors: Marco Volante, Fulvia Daffara, Massimo Terzolo, Martin Fassnacht, Ida Rapa, Antonina Germano, Silviu Sbiera, Paola Sperone, Giorgio V. Scagliotti, Bruno AllolioAbstract:Purpose: Mitotane is the most broadly used systemic therapy for adrenocortical carcinoma (ACC), but its mechanism of action and possible predictors of treatment response are currently poorly defined. Our aim was to evaluate the gene expression of ribonucleotide reductase large subunit 1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) in ACC as potential biomarkers for clinical outcome and response to Mitotane. Experimental Design: Forty-five and 47 tissue samples from two cohorts (Orbassano, Italy; Wuerzburg, Germany) of completely resected ACC were centrally analyzed using real-time PCR for RRM1 and ERCC1 expression. Fifty-four patients received surgery alone and 38 received adjuvant Mitotane after surgery. Clinical and pathologic features were highly comparable in the two series. H295R and SW-13 ACC cell lines were also used for pharmacologic tests. Results: ERCC1 gene expression was not associated to clinical outcome. In contrast, high RRM1 gene expression was associated to shorter disease-free survival (DFS) and overall survival at both univariate and multivariate analysis. In patients with low RRM1 gene expression, adjuvant Mitotane was associated with improved DFS, whereas this effect was lost in cases with high RMM1 expression. In vitro Mitotane induced strong up regulation of RRM1 transcription (up to 25-fold increase) in Mitotane-insensitive SW-13 but not in Mitotane-sensitive H295R cells. Furthermore, RRM1 silencing in SW-13 cells induced sensitivity to Mitotane. Conclusion: Our in vitro and in vivo data indicate that RRM1 gene expression is functionally associated to Mitotane sensitivity and support a possible role of RRM1 determination as a novel molecular biomarker predicting response to adjuvant Mitotane in ACC. Clin Cancer Res; 18(12); 3452–61. ©2012 AACR .
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Therapeutic concentrations of Mitotane inhibit thyrotroph cell viability and TSH secretion in a mouse cell line model
'Society for Endocrinology', 2010Co-Authors: Erica Gentilin, Fulvia Daffara, Massimo Terzolo, Giuseppe Reimondo, Maria Rosaria Ambrosio, Gianni Carandina, Ettore Degli C Uberti, Maria Chiara ZatelliAbstract:Mitotane therapy is associated with many side effects, including thyroid function perturbations mimicking central hypothyroidism, possibly due to laboratory test interference or pituitary direct effects of Mitotane. Therefore, we aimed at investigating whether increasing concentrations of Mitotane in the therapeutic range might interfere with thyroid hormone assays and evaluate the effects of Mitotane on a mouse TSH- producing pituitary cell line. TSH, FT4 and FT3 levels do not significantly change in sera from hypo-, hyper- or euthyroid patients after addition of Mitotane at concentrations in the therapeutic window. In the mouse TαT1 cell line Mitotane inhibits both TSH expression and secretion, blocks TSH response to TRH and reduces cell viability, inducing apoptosis at concentrations in the therapeutic window. TRH is not capable of rescuing TαT1 cells from the inhibitory effects of Mitotane on TSH expression and secretion, that appear after short time treatment and persist over time. Our results demonstrate that Mitotane does not interfere with thyroid hormone laboratory tests but directly reduces both secretory activity and cell viability on pituitary TSH-secreting mouse cells. These data represent a possible explanation of the biochemical picture consistent with central hypothyroidism in patients undergoing Mitotane therapy, and open new perspectives on the direct pituitary effects of this drug
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Prospective evaluation of Mitotane toxicity in adrenocortical cancer patients treated adjuvantly
Endocrine-related cancer, 2008Co-Authors: Fulvia Daffara, Silvia De Francia, Marco Volante, Francesco Di Carlo, Barbara Zaggia, Giuseppe Reimondo, Emiliano Aroasio, Francesco Porpiglia, A. Termine, Luigi DogliottiAbstract:Toxicity of adjuvant Mitotane treatment is poorly known; thus, our aim was to assess prospectively the unwanted effects of adjuvant Mitotane treatment and correlate the findings with Mitotane concentrations. Seventeen consecutive patients who were treated with Mitotane after radical resection of adrenocortical cancer (ACC) from 1999 to 2005 underwent physical examination, routine laboratory evaluation, monitoring of Mitotane concentrations, and a hormonal work-up at baseline and every 3 months till ACC relapse or study end (December 2007). Mitotane toxicity was graded using NCI CTCAE criteria. All biochemical measurements were performed at our center and plasma Mitotane was measured by an in-house HPLC assay. All the patients reached Mitotane concentrations >14 mg/l and none of them discontinued definitively Mitotane for toxicity; 14 patients maintained consistently elevated Mitotane concentrations despite tapering of the drug. Side effects occurred in all patients but were manageable with palliative treatment and adjustment of hormone replacement therapy. Mitotane affected adrenal steroidogenesis with a more remarkable inhibition of cortisol and DHEAS than aldosterone. Mitotane induced either perturbation of thyroid function mimicking central hypothyroidism or, in male patients, inhibition of testosterone secretion. The discrepancy between salivary and serum cortisol, as well as between total and free testosterone, is due to the Mitotane-induced increase in hormone-binding proteins which complicates interpretation of hormone measurements. A low-dose monitored regimen of Mitotane is tolerable and able to maintain elevated drug concentrations in the long term. Mitotane exerts a complex effect on the endocrine system that may require multiple hormone replacement therapy.
Jacques Young - One of the best experts on this subject based on the ideXlab platform.
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Foetal exposure to Mitotane/Op'DDD: Post-natal study of four children
Clinical Endocrinology, 2018Co-Authors: D Magkou, Claire Bouvattier, Claire Douillard, Capucine De Marcellus, Laure Cazabat, Maxime Gerard, Marie-laure Raffin-sanson, Christine Do Cao, Jacques YoungAbstract:Objective: Mitotane/Op'DDD is used in the treatment of adrenocortical carcinoma and for other causes of hypercortisolism. Mitotane inhibits cortisol secretion and displays adrenolytic and antitumor actions. This compound is a metabolite of the pesticide and endocrine disruptor DDT (dichlorodiphenyltrichloroethane) and is classified among teratogenic compounds worldwide. However, little is known about its effects on human development. Design: The outcome of four children exposed to Mitotane during their intrauterine life was examined. Patients: Patients having conceived while taking Mitotane, or with detectable Mitotane plasma levels, were retrospectively recruited via the French COMETE and FIRENDO networks. Measurements: Mitotane in maternal plasma, adrenocortical hormones in children. Results: Three women treated with Mitotane gave birth to four children. During early pregnancy, all patients had detectable Mitotane plasma levels (0.9, 2.4 and 6.7 mg/L, respectively). During pregnancy, no foetal malformations were detected. The four exposed newborns presented at birth with apparently normal adrenal function and genitalia. One twin female had a low birthweight. Evaluation at birth and after 3 months, 2 years and 7 years of follow-up showed no significant neurological abnormality. Evaluation of adrenocortical functions showed no cortisol deficiency. Conclusions: Unexpectedly, exposure of these four children to Mitotane during foetal life seemed to have no clear teratogenic effect. However, considering the sub-therapeutic Mitotane concentrations used here, the small number of cases, and because long-term follow-up is unknown, we strongly advise not to take Mitotane during pregnancy and still recommend avoiding pregnancy, at least as long as Mitotane plasma levels remain detectable. © 2018 John Wiley & Sons Ltd
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foetal exposure to Mitotane op ddd post natal study of four children
Clinical Endocrinology, 2018Co-Authors: D Magkou, Christine Do Cao, Claire Bouvattier, Claire Douillard, Capucine De Marcellus, Laure Cazabat, Maxime Gerard, M L Raffinsanson, Jacques YoungAbstract:OBJECTIVE Mitotane/Op'DDD is used in the treatment of adrenocortical carcinoma and for other causes of hypercortisolism. Mitotane inhibits cortisol secretion and displays adrenolytic and antitumor actions. This compound is a metabolite of the pesticide and endocrine disruptor DDT (dichlorodiphenyltrichloroethane) and is classified among teratogenic compounds worldwide. However, little is known about its effects on human development. DESIGN The outcome of four children exposed to Mitotane during their intrauterine life was examined. PATIENTS Patients having conceived while taking Mitotane, or with detectable Mitotane plasma levels, were retrospectively recruited via the French COMETE and FIRENDO networks. MEASUREMENTS Mitotane in maternal plasma, adrenocortical hormones in children. RESULTS Three women treated with Mitotane gave birth to four children. During early pregnancy, all patients had detectable Mitotane plasma levels (0.9, 2.4 and 6.7 mg/L, respectively). During pregnancy, no foetal malformations were detected. The four exposed newborns presented at birth with apparently normal adrenal function and genitalia. One twin female had a low birthweight. Evaluation at birth and after 3 months, 2 years and 7 years of follow-up showed no significant neurological abnormality. Evaluation of adrenocortical functions showed no cortisol deficiency. CONCLUSIONS Unexpectedly, exposure of these four children to Mitotane during foetal life seemed to have no clear teratogenic effect. However, considering the sub-therapeutic Mitotane concentrations used here, the small number of cases, and because long-term follow-up is unknown, we strongly advise not to take Mitotane during pregnancy and still recommend avoiding pregnancy, at least as long as Mitotane plasma levels remain detectable.
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Foetal exposure to Mitotane/Op'DDD: Post-natal study of four children.
Clinical endocrinology, 2018Co-Authors: D Magkou, Christine Do Cao, Claire Bouvattier, Claire Douillard, Capucine De Marcellus, Laure Cazabat, Maxime Gerard, Marie-laure Raffin-sanson, Jacques YoungAbstract:OBJECTIVE Mitotane/Op'DDD is used in the treatment of adrenocortical carcinoma and for other causes of hypercortisolism. Mitotane inhibits cortisol secretion and displays adrenolytic and antitumor actions. This compound is a metabolite of the pesticide and endocrine disruptor DDT (dichlorodiphenyltrichloroethane) and is classified among teratogenic compounds worldwide. However, little is known about its effects on human development. DESIGN The outcome of four children exposed to Mitotane during their intrauterine life was examined. PATIENTS Patients having conceived while taking Mitotane, or with detectable Mitotane plasma levels, were retrospectively recruited via the French COMETE and FIRENDO networks. MEASUREMENTS Mitotane in maternal plasma, adrenocortical hormones in children. RESULTS Three women treated with Mitotane gave birth to four children. During early pregnancy, all patients had detectable Mitotane plasma levels (0.9, 2.4 and 6.7 mg/L, respectively). During pregnancy, no foetal malformations were detected. The four exposed newborns presented at birth with apparently normal adrenal function and genitalia. One twin female had a low birthweight. Evaluation at birth and after 3 months, 2 years and 7 years of follow-up showed no significant neurological abnormality. Evaluation of adrenocortical functions showed no cortisol deficiency. CONCLUSIONS Unexpectedly, exposure of these four children to Mitotane during foetal life seemed to have no clear teratogenic effect. However, considering the sub-therapeutic Mitotane concentrations used here, the small number of cases, and because long-term follow-up is unknown, we strongly advise not to take Mitotane during pregnancy and still recommend avoiding pregnancy, at least as long as Mitotane plasma levels remain detectable.
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la fraction non liee aux lipoproteines du Mitotane est plus cytotoxique consequences sur la prise en charge du corticosurrenalome
Annales D Endocrinologie, 2015Co-Authors: Segolene Hescot, Jacques Young, Angelo Paci, Atmane Seck, Maryse Guerin, Thierry Huby, Eric Baudin, Marc LombèsAbstract:Le Mitotane (o,p′-DDD), traitement de choix du corticosurrenalome, est une molecule lipophile transportee par les lipoproteines et s’accumulant dans les tissus riches en graisses. Nous avons evalue in vivo et in vitro l’influence des lipoproteines sur les proprietes pharmacologiques du Mitotane, en mesurant le contenu intra-tumoral de Mitotane obtenus chez des patients et en etudiant l’impact du Mitotane non liee aux fractions lipoproteiques sur la proliferation et l’apoptose des cellules humaines corticosurrenaliennes H295R. Enfin, une etude retrospective de patients traites ou non par statines a ete realisee. Il n’existe aucune association entre les concentrations intra-surrenaliennes d’o,p′DDD (6 patients) et l’expression des genes codant pour les recepteurs aux lipoproteines SrB1 et LDL-R, excluant un role majeur des transporteurs du HDL ou LDL cholesterol dans le transport intracellulaire du Mitotane. Les etudes in vitro montrent un effet antiproliferatif (test WST1) et pro-apoptotique (activite caspase), significativement plus marque lorsque les cellules sont cultivees en l’absence de lipoproteines LDL ou HDL. Le contenu intracellulaire, essentiellement intramitochondrial (90 %), du Mitotane mesure par GC-MS est significativement plus important lorsque l’exposition au Mitotane s’effectue en l’absence de lipoproteines. Ceci suggere que le Mitotane libre est pharmacologiquement plus actif. L’etude retrospective de 26 patients porteurs de corticosurrenalome de stade IV revele qu’un traitement par statines est significativement associe a un meilleur controle tumoral a 6 mois par le Mitotane. Nos etudes montrent que le Mitotane libre exerce des effets cytotoxiques plus marques. Les patients pourraient alors beneficier de strategies therapeutiques visant a augmenter la fraction de Mitotane libre.
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Lipoprotein-Free Mitotane Exerts High Cytotoxic Activity in Adrenocortical Carcinoma
The Journal of clinical endocrinology and metabolism, 2015Co-Authors: Segolene Hescot, Jacques Young, Angelo Paci, Atmane Seck, Maryse Guerin, Florence Cockenpot, Thierry Huby, Sophie Broutin, Eric Baudin, Marc LombèsAbstract:Mitotane (o,p'-DDD), the only approved drug for advanced adrenocortical carcinoma (ACC), is a lipophilic agent that accumulates into circulating lipoprotein fractions and high-lipid-containing tissues. The aim of our study was to evaluate the in vivo and in vitro biological implication of serum lipoproteins on pharmacological action of Mitotane. Distribution and concentration of Mitotane were studied in plasma and adrenal tissue samples from Mitotane-treated patients. The effect of lipoprotein-bound or lipoprotein-free (LP-F) Mitotane was analyzed on proliferation and apoptosis of human adrenocortical H295R cells. A retrospective study of patients with ACC treated or not with statins was also performed. o,p'-DDD distribution among very low-density lipoprotein, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and LP-F fractions obtained after plasma ultracentrifugation of 23 of Mitotane-treated patients was widely distributed in each subfraction. A positive correlation was observed between Mitotane levels in plasma and in LDL, HDL, but also LP-F compartment. Intratumor o,p'-DDD concentrations in five ACC samples of Mitotane-treated patients were found to be independent of cholesterol transporter expression, scavenger receptors, and LDL receptors. In vitro studies showed significant higher antiproliferative and proapoptotic effects and higher cell and mitochondrial uptake of Mitotane when H295R cells were grown in LP-F medium. Finally, retrospective study of an ACC cohort of 26 Mitotane-treated patients revealed that statin therapy was significantly associated with a higher rate of tumor control. Altogether, our in vitro and in vivo studies provided compelling evidence for a greater efficacy of LP-F Mitotane. Patients with ACC may thus benefit from therapeutic strategies that aim to increase LP-F Mitotane fraction.
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prolonged adrenal insufficiency after the discontinuation of Mitotane therapy
Endocrine‚ Metabolic & Immune Disorders-Drug Targets, 2020Co-Authors: Leonardo Muratori, Giorgio V. Scagliotti, Giuseppe Reimondo, Anna Pia, Soraya Puglisi, C Pisano, Anna La Salvia, Paola SperoneAbstract:Introduction Adrenocortical carcinoma (ACC) is a rare neoplasm characterized by a high risk of recurrence after radical resection. The role of adjuvant systemic therapy in radically resected patients is unclear. Mitotane, a steroidogenesis inhibitor, is the only drug approved for the systemic treatment of advanced ACC. In 2007, a retrospective case-control study provided the evidence that Mitotane, administered for two years after successful surgery, could prolong recurrence-free survival. Adrenal insufficiency (AI), which occurs in almost all patients during the first 12 months of treatment, is an expected side effect of Mitotane and requires steroid replacement therapy. Due to its long halflife, Mitotane-induced AI persists several months after treatment discontinuation and is managed by cautious tapering of glucocorticoid replacement therapy. Results We report a case of symptomatic AI diagnosed after a severe allergic reaction occurring three years after the discontinuation of adjuvant Mitotane therapy. Conclusion The case suggests that Mitotane-induced AI should be monitored for a long time to asses full recovery of adrenal function, in order to prevent adrenal crises.
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Prolonged Adrenal Insufficiency After the Discontinuation of Mitotane Therapy.
Endocrine metabolic & immune disorders drug targets, 2020Co-Authors: Leonardo Muratori, Giorgio V. Scagliotti, Giuseppe Reimondo, Anna Pia, Soraya Puglisi, C Pisano, Anna La Salvia, Paola SperoneAbstract:Adrenocortical carcinoma (ACC) is a rare neoplasm characterized by a high risk of recurrence after radical resection. The role of adjuvant systemic therapy in radically resected patients is unclear. Mitotane, a steroidogenesis inhibitor, is the only drug approved for the systemic treatment of advanced ACC. In 2007, a retrospective case-control study provided the evidence that Mitotane, administered for two years after successful surgery, could prolong recurrence-free survival. Adrenal insufficiency (AI), which occurs in almost all patients during the first 12 months of treatment, is an expected side effect of Mitotane and requires steroid replacement therapy. Due to its long halflife, Mitotane-induced AI persists several months after treatment discontinuation and is managed by cautious tapering of glucocorticoid replacement therapy. We report a case of symptomatic AI diagnosed after a severe allergic reaction occurring three years after the discontinuation of adjuvant Mitotane therapy. The case suggests that Mitotane-induced AI should be monitored for a long time to asses full recovery of adrenal function, in order to prevent adrenal crises. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
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New perspectives for Mitotane treatment of adrenocortical carcinoma.
Best practice & research. Clinical endocrinology & metabolism, 2020Co-Authors: Soraya Puglisi, Giuseppe Reimondo, Paola Perotti, Anna Pia, Anna Calabrese, Vittoria Basile, Massimo TerzoloAbstract:Adrenocortical carcinoma (ACC) is an aggressive cancer characterized by poor survival. Apart from radical surgery, there is a limited range of therapeutic options and Mitotane remains the cornerstone of medical treatment of ACC in either adjuvant or palliative settings. The aim of adjuvant Mitotane therapy is to reduce the risk of ACC recurrence following surgical removal of the tumor. Use of Mitotane in an adjuvant setting is off-label, but the recent guidelines endorsed by the European Society of Endocrinology (ESE) and the European Network for the Study of Adrenal Tumors (ENSAT) recommend it in ACC patients at high risk of recurrence. The palliative use of Mitotane for treatment of advanced ACC aims at controlling tumor progression and, when present, hormone secretion. In this clinical setting, Mitotane is used in association with chemotherapy to treat the more aggressive forms, while Mitotane monotherapy is reserved for less progressive ACC. Many years after its introduction in clinical practice, there are still uncertainties surrounding the use of this old drug and the derived benefits. Moreover, physicians who use Mitotane should recognize and manage the systemic effects of the drug that need a complex supporting therapy.
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effects of Mitotane on the hypothalamic pituitary adrenal axis in patients with adrenocortical carcinoma
European Journal of Endocrinology, 2017Co-Authors: Giuseppe Reimondo, Silvia De Francia, Marco Volante, Barbara Zaggia, Laura Saba, Paola Perotti, Maria Chiara Zatelli, Soraya Puglisi, Vittoria Basile, Salvatore CannavòAbstract:Objective Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency. Recent studies in vitro have also documented a direct inhibitory effect of Mitotane at the pituitary level. The present study was aimed to assess the hypothalamic-pituitary-adrenal axis in patients with ACC receiving Mitotane. Design and methods We prospectively enrolled 16 patients on adjuvant treatment with Mitotane after radical surgical resection of ACC, who underwent standard hormone evaluation and h-CRH stimulation. A group of 10 patients with primary adrenal insufficiency (PAI) served as controls for the CRH test. Results We demonstrated a close correlation between cortisol-binding globulin (CBG) and plasma Mitotane levels, and a non-significant trend between Mitotane dose and either serum or salivary cortisol in ACC patients. We did not find any correlation between the dose of cortisone acetate and either ACTH or cortisol levels. ACTH levels were significantly higher in patients with PAI than that in patients with ACC, both in baseline conditions (88.99 (11.04-275.00) vs 24.53 (6.16-121.88) pmol/L, P = 0.031) and following CRH (158.40 (34.32-275.00) vs 67.43 (8.8-179.52) pmol/L P = 0.016). Conclusions The observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that Mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels. In conclusion, the present study shows that Mitotane affects the HPA axis at multiple levels and no single biomarker may be used for the assessment of adrenal insufficiency.
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Effects of Mitotane on the hypothalamic–pituitary–adrenal axis in patients with adrenocortical carcinoma
European journal of endocrinology, 2017Co-Authors: Giuseppe Reimondo, Silvia De Francia, Marco Volante, Barbara Zaggia, Laura Saba, Paola Perotti, Maria Chiara Zatelli, Soraya Puglisi, Vittoria Basile, Salvatore CannavòAbstract:Objective Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency. Recent studies in vitro have also documented a direct inhibitory effect of Mitotane at the pituitary level. The present study was aimed to assess the hypothalamic-pituitary-adrenal axis in patients with ACC receiving Mitotane. Design and methods We prospectively enrolled 16 patients on adjuvant treatment with Mitotane after radical surgical resection of ACC, who underwent standard hormone evaluation and h-CRH stimulation. A group of 10 patients with primary adrenal insufficiency (PAI) served as controls for the CRH test. Results We demonstrated a close correlation between cortisol-binding globulin (CBG) and plasma Mitotane levels, and a non-significant trend between Mitotane dose and either serum or salivary cortisol in ACC patients. We did not find any correlation between the dose of cortisone acetate and either ACTH or cortisol levels. ACTH levels were significantly higher in patients with PAI than that in patients with ACC, both in baseline conditions (88.99 (11.04-275.00) vs 24.53 (6.16-121.88) pmol/L, P = 0.031) and following CRH (158.40 (34.32-275.00) vs 67.43 (8.8-179.52) pmol/L P = 0.016). Conclusions The observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that Mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels. In conclusion, the present study shows that Mitotane affects the HPA axis at multiple levels and no single biomarker may be used for the assessment of adrenal insufficiency.