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Journal of Physiology and Pharmacology... Feb 2017Adrenocortical carcinoma is a rare disease with poor prognosis. Mitotane is the most effective agent in post-operative treatment (or when inoperable). It selectively... (Review)
Review
Adrenocortical carcinoma is a rare disease with poor prognosis. Mitotane is the most effective agent in post-operative treatment (or when inoperable). It selectively limits growth and bioactivity of adrenal tissue. Despite 60 years of use, the basis for its action has yet to be convincingly established. This review summarizes current knowledge of mitotane effects, based on studies on adrenal tissue and primary cell cultures, with emphasis on more recent studies of cell lines. We consider features of the adrenal cortex that might explain mitotane selectivity, and review effects on non-adrenal cells. Since the most clear-cut mitotane effects have been observed for mitochondria, this topic is the core of the review. Mitochondria present unique characteristics in steroidogenic tissue and are known to be important in malignancy development and apoptosis. We look at the evidence for mitotane activation within mitochondria, its impact on mitochondrial energy metabolism and other cellular processes as well as on downstream effects in the cell, such as apoptosis initiation. Further genomic and proteomic investigative studies are likely to yield useful results.
Topics: Adrenal Cortex; Adrenocortical Carcinoma; Animals; Antineoplastic Agents, Hormonal; Apoptosis; Cell Death; Humans; Mitochondria; Mitotane; Proteins; Proteome; Steroids
PubMed: 28456766
DOI: No ID Found -
British Journal of Clinical Pharmacology Jul 2021Mitotane is the only adrenolytic drug approved by the Food and Drug Administration for treating adrenocortical carcinoma (ACC). This drug has cytotoxic effects on tumour... (Review)
Review
Mitotane is the only adrenolytic drug approved by the Food and Drug Administration for treating adrenocortical carcinoma (ACC). This drug has cytotoxic effects on tumour tissues; it induces cell death and antisecretory effects on adrenal cells by inhibiting the synthesis of adrenocortical steroids, which are involved in the pathogenesis of ACC. However, high doses of mitotane are usually necessary to reach the therapeutic plasma concentration, which may result in several adverse effects. This suggests that important pharmacological processes, such as first pass metabolism, tissue accumulation and extensive time for drug elimination, are associated with mitotane administration. Few studies have reported the pharmacological aspects and therapeutic effects of mitotane. Therefore, the aim of this review was to summarize the chemistry, pharmacokinetics and pharmacodynamics, and therapeutic and toxic effects of mitotane. This review also discusses new perspectives of mitotane formulation that are currently under investigation. Understanding the pharmacological profile of mitotane can improve the monitoring and efficacy of this drug in ACC treatment and can provide useful information for the development of new drugs with specific action against ACC with fewer adverse effects.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Humans; Mitotane; Steroids
PubMed: 33382119
DOI: 10.1111/bcp.14721 -
European Journal of Drug Metabolism and... Sep 2021Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal gland cortex with a heterogeneous but overall dismal prognosis in advanced stages. For... (Review)
Review
Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal gland cortex with a heterogeneous but overall dismal prognosis in advanced stages. For more than 50 years, mitotane has remained a cornerstone for the treatment of ACC as adjuvant and palliative therapy. It has a very poor aqueous solubility of 0.1 mg/l and high partition coefficient in octanol/water (log P) value of 6. The commercially available dosage form is 500 mg tablets (Lysodren). Even at doses up to 6 g/day (12 tablets in divided doses) for several months, > 50% patients do not achieve therapeutic plasma concentration > 14 mg/l due to poor water solubility, large volume of distribution and inter/intra-individual variability in bioavailability. This article aims to give a concise update of the clinical challenges associated with the administration of high-dose mitotane oral therapy which encompass the issues of poor bioavailability, difficult-to-predict pharmacokinetics and associated adverse events. Moreover, we present recent efforts to improve mitotane formulations. Their success has been limited, and we therefore propose an injectable mitotane formulation instead of oral administration, which could bypass many of the main issues associated with high-dose oral mitotane therapy. A parenteral administration of mitotane could not only help to alleviate the adverse effects but also circumvent the variable oral absorption, give better control over therapeutic plasma mitotane concentration and potentially shorten the time to achieve therapeutic drug plasma concentrations considerably.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Animals; Antineoplastic Agents, Hormonal; Biological Availability; Humans; Mitotane; Solubility; Tissue Distribution
PubMed: 34287806
DOI: 10.1007/s13318-021-00700-5 -
Current Opinion in Investigational... Apr 2005Adrenocortical carcinoma (ACC) is a rare neoplasm with poor prognosis. Mitotane is the only adrenal-specific agent available for the treatment of ACC, and although it... (Review)
Review
Adrenocortical carcinoma (ACC) is a rare neoplasm with poor prognosis. Mitotane is the only adrenal-specific agent available for the treatment of ACC, and although it has been used for several decades, many of its pharmacological properties, as well as its exact mechanism of action, remain to be fully elucidated. It is known that metabolic activation is essential for the adrenolytic activity of mitotane. Most published clinical reports of mitotane use are retrospective analyses of small numbers of patients, however, the collective findings of these studies indicate that mitotane has activity against ACC; in approximately 25% of cases mitotane led to an objective tumor regression and, in the majority of patients, control of hormone excess could be achieved. Side effects occur frequently during mitotane treatment and they mainly affect the gastrointestinal tract and the central nervous system. As not all patients respond to mitotane therapy, it is one of the challenges for the future to define the subset of patients who do respond to mitotane to avoid treatment of patients who are unlikely to respond to this toxic drug. The pharmacological properties of mitotane and its efficacy in the treatment of ACC are analyzed in this review.
Topics: Adrenocortical Carcinoma; Humans; Mitotane
PubMed: 15898346
DOI: No ID Found -
Endocrinology Sep 2022Adrenocortical carcinoma (ACC) is a rare aggressive cancer with low overall survival. Adjuvant mitotane improves survival but is limited by poor response rates and...
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare aggressive cancer with low overall survival. Adjuvant mitotane improves survival but is limited by poor response rates and resistance. Mitotane's efficacy is attributed to the accumulation of toxic free cholesterol, predominantly through cholesterol storage inhibition. However, targeting this pathway has proven unsuccessful. We hypothesize that mitotane-induced free-cholesterol accumulation is also mediated through enhanced breakdown of lipid droplets.
METHODOLOGY
ATCC-H295R (mitotane-sensitive) and MUC-1 (mitotane-resistant) ACC cells were evaluated for lipid content using specific BODIPY dyes. Protein expression was evaluated by immunoblotting and flow cytometry. Cell viability was measured by quantifying propidium iodide-positive cells following mitotane treatment and pharmacological inhibitors of lipolysis.
RESULTS
H295R and MUC-1 cells demonstrated similar neutral lipid droplet numbers at baseline. However, evaluation of lipid machinery demonstrated distinct profiles in each model. Analysis of intracellular lipid droplet content showed H295R cells preferentially store cholesteryl esters, whereas MUC-1 cells store triacylglycerol. Decreased lipid droplets were associated with increased lipolysis in H295R and in MUC-1 at toxic mitotane concentrations. Pharmacological inhibition of lipolysis attenuated mitotane-induced toxicity in both models.
CONCLUSION
We highlight that lipid droplet breakdown and activation of lipolysis represent a putative additional mechanism for mitotane-induced cytotoxicity in ACC. Further understanding of cholesterol and lipids in ACC offers potential novel therapeutic exploitation, especially in mitotane-resistant disease.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antineoplastic Agents, Hormonal; Cell Line, Tumor; Cholesterol; Humans; Lipid Droplets; Lipolysis; Mitotane
PubMed: 35797592
DOI: 10.1210/endocr/bqac102 -
Current Opinion in Endocrinology,... Jun 2014Description of novel findings about the mechanism of action of mitotane and its activity as an adjunctive postoperative measure, or for treatment of advanced... (Review)
Review
PURPOSE OF REVIEW
Description of novel findings about the mechanism of action of mitotane and its activity as an adjunctive postoperative measure, or for treatment of advanced adrenocortical carcinoma.
RECENT FINDINGS
Several in-vitro studies have shown that mitotane suppresses gene transcription of different enzymatic steps of the steroidogenetic pathway. Moreover, mitotane induces CYP3A4 expression, thus accelerating the metabolic clearance of a variety of drugs including steroids. Retrospective studies provided evidence that adjunctive mitotane can prolong recurrence-free survival of treated patients. The concept of a therapeutic window of mitotane plasma concentrations was confirmed also for adjunctive treatment, but the relationship between mitotane concentration and given dose is loose. Genetic variability of the P450-dependent enzymes metabolizing mitotane may explain individual differences.
SUMMARY
Mitotane concentration of 14-20 mg/l should be reached and maintained during treatment also in an adjunctive setting. In advanced adrenocortical carcinoma, a high-dose starting regimen should be employed when mitotane is used as monotherapy. The combination of mitotane with other drugs should consider the possibility of pharmacologic interactions due to mitotane-induced activation of drug metabolism. This concept applies also to steroid replacement in mitotane-treated patients, who need higher doses to adjust for increased steroid metabolism.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Male; Mitotane; Neoplasm Recurrence, Local; Treatment Outcome
PubMed: 24732405
DOI: 10.1097/MED.0000000000000056 -
The Journal of Clinical Endocrinology... Aug 2023Central hypothyroidism was described previously in mitotane-treated patients but data on its prevalence and time of occurrence are limited. (Review)
Review
CONTEXT
Central hypothyroidism was described previously in mitotane-treated patients but data on its prevalence and time of occurrence are limited.
OBJECTIVE
To better characterize thyroid hormone insufficiency in patients exposed to mitotane.
METHODS
We reviewed medical records of patients from 2 academic centers in Montreal (Canada) and Toulouse (France) with exposure to mitotane therapy for adrenocortical cancer between 1995 and 2020. We analyzed the thyroid function parameters during and after treatment.
RESULTS
In our cohort of 83 patients, 17 were excluded because of preexisting primary hypothyroidism or drug-induced hypothyroidism. During follow-up, 3/66 patients maintained a normal thyroid function and 63/66 developed central hypothyroidism. Among those 63 patients, 56 presented with an inappropriately normal or low TSH and 7 with a mildly elevated TSH. The onset of hypothyroidism was: <3 months in 33.3%, 3 to 6 months in 19.1%, 6 to 9 months in 14.3%, and 9 to 12 months in 9.5%. At least 14.3% of cases occurred after 12 months of exposure, and 6 patients had an undetermined time of occurrence. Over time, 27 patients stopped mitotane and partial (42.3%) or complete (23.1%) recovery from hypothyroidism was observed, mainly in the first 2 years after mitotane discontinuation.
CONCLUSION
Mitotane therapy is frequently associated with new onset of central hypothyroidism with a prevalence of 95.5%. Most cases occurred in the first year of treatment. Partial or full recovery of thyroid function occurs in 65.4% of cases. This study supports the importance of systematic monitoring of TSH and free T4 levels during and following discontinuation of mitotane therapy.
Topics: Humans; Mitotane; Prevalence; Antineoplastic Agents, Hormonal; Hypothyroidism; Adrenal Cortex Neoplasms; Thyrotropin; Adrenocortical Carcinoma
PubMed: 36856782
DOI: 10.1210/clinem/dgad115 -
The Lancet. Diabetes & Endocrinology Oct 2023Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of... (Randomized Controlled Trial)
Randomized Controlled Trial Observational Study
Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study.
BACKGROUND
Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of recurrence is not high. We aimed to assess the efficacy and safety of adjuvant mitotane compared with surveillance alone following complete tumour resection in patients with adrenocortical carcinoma considered to be at low to intermediate risk of recurrence.
METHODS
ADIUVO was a multicentre, open-label, parallel, randomised, phase 3 trial done in 23 centres across seven countries. Patients aged 18 years or older with adrenocortical carcinoma and low to intermediate risk of recurrence (R0, stage I-III, and Ki67 ≤10%) were randomly assigned to adjuvant oral mitotane two or three times daily (the dose was adjusted by the local investigator with the target of reaching and maintaining plasma mitotane concentrations of 14-20 mg/L) for 2 years or surveillance alone. All consecutive patients at 14 study centres fulfilling the eligibility criteria of the ADIUVO trial who refused randomisation and agreed on data collection via the European Network for the Study of Adrenal Tumors adrenocortical carcinoma registry were included prospectively in the ADIUVO Observational study. The primary endpoint was recurrence-free survival, defined as the time from randomisation to the first radiological evidence of recurrence or death from any cause (whichever occurred first), assessed in all randomly assigned patients by intention to treat. Overall survival, defined as time from the date of randomisation to the date of death from any cause, was a secondary endpoint analysed by intention to treat in all randomly assigned patients. Safety was assessed in all patients who adhered to the assigned regimen, which was defined by taking at least one tablet of mitotane in the mitotane group and no mitotane at all in the surveillance group. The ADIUVO trial is registered with ClinicalTrials.gov, NCT00777244, and is now complete.
FINDINGS
Between Oct 23, 2008, and Dec 27, 2018, 45 patients were randomly assigned to mitotane and 46 to surveillance alone. Because the study was discontinued prematurely, 5-year recurrence-free and overall survival are reported instead of recurrence-free and overall survival as defined in the protocol. 5-year recurrence-free survival was 79% (95% CI 67-94) in the mitotane group and 75% (63-90) in the surveillance group (hazard ratio 0·74 [95% CI 0·30-1·85]). Two people in the mitotane group and five people in the surveillance group died, and 5-year overall survival was not significantly different (95% [95% CI 89-100] in the mitotane group and 86% [74-100] in the surveillance group). All 42 patients who received mitotane had adverse events, and eight (19%) discontinued treatment. There were no grade 4 adverse events or treatment-related deaths.
INTERPRETATION
Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment.
FUNDING
AIFA, ENSAT Cancer Health F2-2010-259735 programme, Deutsche Forschungsgemeinschaft, Cancer Research UK, and the French Ministry of Health.
Topics: Humans; Mitotane; Adrenocortical Carcinoma; Disease-Free Survival; Adrenal Cortex Neoplasms
PubMed: 37619579
DOI: 10.1016/S2213-8587(23)00193-6 -
Expert Opinion on Drug Metabolism &... Jun 2021Mitotane is the only drug registered specifically for adrenocortical carcinoma. Finding the optimal dose for a patient is difficult due to large differences in... (Review)
Review
INTRODUCTION
Mitotane is the only drug registered specifically for adrenocortical carcinoma. Finding the optimal dose for a patient is difficult due to large differences in bioavailability, toxicity and effect. We therefore look to improve personalized dosing of mitotane.
AREAS COVERED
We searched PubMed for studies related to mitotane dosing, pharmacokinetics, pharmacogenetics and combination therapy. Comparison of different dosing strategies have not resulted in an optimal advice. Several computerized pharmacokinetic models have been proposed to predict plasma levels. The current pharmacokinetic models do not explain the full variance in plasma levels. Pharmacogenetics have been proposed to find the unexplained variance. Studies on combination therapy have not yet led to a potential dose adjustment for mitotane.
EXPERT OPINION
Computerized pharmacokinetics models are promising tools to predict plasma levels, further validation is needed. Pharmacogenetics are introduced in these models, but more research is required before clinical application. We believe that in the near future, personalized mitotane dosage will be aided by a validated web-based pharmacokinetic model with good predictive ability based primarily on clinical characteristics, adjustable for actual plasma levels and dosage.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antineoplastic Agents, Hormonal; Computer Simulation; Dose-Response Relationship, Drug; Humans; Mitotane; Models, Biological; Pharmacogenetics; Precision Medicine
PubMed: 33886381
DOI: 10.1080/17425255.2021.1921146 -
Minerva Endocrinologica Mar 2012Adrenocortical carcinoma (ACC) is a rare aggressive endocrine neoplasm characterized by a 5-year survival of less than 50%. Due to the widespread use of imaging... (Review)
Review
Adrenocortical carcinoma (ACC) is a rare aggressive endocrine neoplasm characterized by a 5-year survival of less than 50%. Due to the widespread use of imaging techniques in clinics, ACC is increasingly recognized as an incidentally discovered tumor. Mostly characterized by poor prognosis, ACC is often diagnosed at an advanced stage of disease. Early diagnosis is uncommon; when diagnosed, ACCs are usually large and have invaded adjacent organs, even if metastatic spread to distant sites can be absent. Complete surgical resection is the only potentially curative treatment for patients with localized disease; however, due to a recurrence rate of 50-70% after apparent radical surgery, there is a strong rationale for a concomitant systemic treatment. Adrenolytic therapy with mitotane (o,p›-DDD), administered alone or in combination with others antineoplastic agents, is the primary treatment for patients with advanced ACC and is increasingly used also in an adjuvant setting, even if controversy exists on this issue due to the limitations of the available literature. Despite being in use for many years, the rarity of ACC precluded the organization of randomized trials; thus, many areas of uncertainty and controversy remain regarding the role of this old drug in the clinical management of patients with ACC. The purpose of this paper is to review the current evidence on mitotane treatment in patients with advanced disease and in ACC patients after complete surgical resection as adjuvant treatment.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Adrenal Cortex Neoplasms; Adrenal Insufficiency; Adrenalectomy; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biotransformation; Carcinoma; Chemotherapy, Adjuvant; Clinical Trials as Topic; Delayed Diagnosis; Drug Resistance, Neoplasm; Female; Gastrointestinal Diseases; Humans; Incidental Findings; Male; Mitotane; Molecular Structure; Neoplasm Proteins; Prodrugs; Treatment Outcome
PubMed: 22382612
DOI: No ID Found