mitotane

Summary

Summary: A derivative of the insecticide DICHLORODIPHENYLDICHLOROETHANE that specifically inhibits cells of the adrenal cortex and their production of hormones. It is used to treat adrenocortical tumors and causes CNS damage, but no bone marrow depression.

Top Publications

  1. Hermsen I, Fassnacht M, Terzolo M, Houterman S, Den Hartigh J, Leboulleux S, et al. Plasma concentrations of o,p'DDD, o,p'DDA, and o,p'DDE as predictors of tumor response to mitotane in adrenocortical carcinoma: results of a retrospective ENS@T multicenter study. J Clin Endocrinol Metab. 2011;96:1844-51 pubmed publisher
    In patients with adrenocortical carcinoma (ACC) mitotane activity has been suggested to depend on plasma levels 14 mg/liter or greater and metabolite formation.
  2. Zsippai A, Szabó D, Tömböl Z, Szabó P, Eder K, Pallinger E, et al. Effects of mitotane on gene expression in the adrenocortical cell line NCI-H295R: a microarray study. Pharmacogenomics. 2012;13:1351-61 pubmed publisher
    The adrenolytic agent mitotane is widely used in the treatment of adrenocortical cancer; however, its mechanism of action is poorly elucidated...
  3. Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton P, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007;356:2372-80 pubmed
    ..Whether the use of mitotane is beneficial as an adjuvant treatment has been controversial...
  4. Volante M, Terzolo M, Fassnacht M, Rapa I, Germano A, Sbiera S, et al. Ribonucleotide reductase large subunit (RRM1) gene expression may predict efficacy of adjuvant mitotane in adrenocortical cancer. Clin Cancer Res. 2012;18:3452-61 pubmed publisher
    b>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...
  5. Dickstein G, Shechner C, Nativ O. Adjuvant mitotane in adrenocortical carcinoma. N Engl J Med. 2007;357:1257-8; author reply 1259 pubmed
  6. Berruti A, Terzolo M, Sperone P, Pia A, Della Casa S, Gross D, et al. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer. 2005;12:657-66 pubmed
    To investigate the activity of etoposide, doxorubicin, and cisplatin plus mitotane in the management of advanced adrenocortical carcinoma (ACC) patients, 72 patients with measurable disease not amenable to radical surgery were enrolled in ..
  7. van Erp N, Guchelaar H, Ploeger B, Romijn J, Hartigh J, Gelderblom H. Mitotane has a strong and a durable inducing effect on CYP3A4 activity. Eur J Endocrinol. 2011;164:621-6 pubmed publisher
    The effects of mitotane on the pharmacokinetics (PK) of co-administered drugs are mostly unknown...
  8. Abraham J, Bakke S, Rutt A, Meadows B, Merino M, Alexander R, et al. A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma: continuous infusion doxorubicin, vincristine, and etoposide with daily mitotane as a P-glycoprotein antagonist. Cancer. 2002;94:2333-43 pubmed
    ..Based on in vitro studies demonstrating the efficacy of mitotane as a P-glycoprotein (Pgp) antagonist, and expression of high levels of Pgp in ACC, the authors conducted a study ..
  9. Cerquetti L, Sampaoli C, Amendola D, Bucci B, Misiti S, Raza G, et al. Mitotane sensitizes adrenocortical cancer cells to ionizing radiations by involvement of the cyclin B1/CDK complex in G2 arrest and mismatch repair enzymes modulation. Int J Oncol. 2010;37:493-501 pubmed
    b>Mitotane inhibits steroid synthesis by an action on steroidogenic enzymes, as 11beta-hydroxylase and cholesterol side chain cleavage...

More Information

Publications62

  1. Zatelli M, Gentilin E, Daffara F, Tagliati F, Reimondo G, Carandina G, et al. Therapeutic concentrations of mitotane (o,p'-DDD) inhibit thyrotroph cell viability and TSH expression and secretion in a mouse cell line model. Endocrinology. 2010;151:2453-61 pubmed publisher
    b>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...
  2. Ilias I, Alevizaki M, Philippou G, Anastasiou E, Souvatzoglou A. Sustained remission of metastatic adrenal carcinoma during long-term administration of low-dose mitotane. J Endocrinol Invest. 2001;24:532-5 pubmed
    ..with two female patients suffering from metastatic, recurrent adrenocortical carcinomas, to whom o,p'-DDD (mitotane) was administered for unusually long duration...
  3. Kasperlik Zaluska A. Clinical results of the use of mitotane for adrenocortical carcinoma. Braz J Med Biol Res. 2000;33:1191-6 pubmed
    b>Mitotane (o,p'-DDD) acts mainly as an inhibitor of intramitochondrial pregnenolone and cortisol synthesis. Its adrenolytic effect depends on metabolic activation due to conversion to o,p'-DDA and o,p'-DDE...
  4. Terzolo M, Pia A, Berruti A, Osella G, Ali A, Carbone V, et al. Low-dose monitored mitotane treatment achieves the therapeutic range with manageable side effects in patients with adrenocortical cancer. J Clin Endocrinol Metab. 2000;85:2234-8 pubmed
    Eight patients with adrenocortical cancer were treated with low doses of mitotane (2-3 g daily) while monitoring drug plasma levels...
  5. Wangberg B, Khorram Manesh A, Jansson S, Nilsson B, Nilsson O, Jakobsson C, et al. The long-term survival in adrenocortical carcinoma with active surgical management and use of monitored mitotane. Endocr Relat Cancer. 2010;17:265-72 pubmed publisher
    ..Adjuvant treatment with the adrenolytic drug mitotane has been attempted, but not proven to prevent from recurrence...
  6. Grubbs E, Callender G, Xing Y, Perrier N, Evans D, Phan A, et al. Recurrence of adrenal cortical carcinoma following resection: surgery alone can achieve results equal to surgery plus mitotane. Ann Surg Oncol. 2010;17:263-70 pubmed publisher
    A recent nonrandomized interinstitutional study reported that adjuvant mitotane following surgery for adrenocortical carcinoma (ACC) was associated with decreased recurrence...
  7. Schteingart D, Sinsheimer J, Benitez R, Homan D, Johnson T, Counsell R. Structural requirements for mitotane activity: development of analogs for treatment of adrenal cancer. Anticancer Res. 2012;32:2711-20 pubmed
    b>Mitotane is used in adrenal cancer as adjuvant therapy, monotherapy or combined with other cytotoxic agents in advanced disease, but only 30% of patients respond...
  8. Daffara F, De Francia S, Reimondo G, Zaggia B, Aroasio E, Porpiglia F, et al. Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly. Endocr Relat Cancer. 2008;15:1043-53 pubmed publisher
    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...
  9. Cerquetti L, Bucci B, Marchese R, Misiti S, de Paula U, Miceli R, et al. Mitotane increases the radiotherapy inhibitory effect and induces G2-arrest in combined treatment on both H295R and SW13 adrenocortical cell lines. Endocr Relat Cancer. 2008;15:623-34 pubmed publisher
    b>Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane (o,p'-DDD) is an agent with adrenotoxic effect, which is able to block cortisol synthesis...
  10. Gonzalez R, Tamm E, Ng C, Phan A, Vassilopoulou Sellin R, Perrier N, et al. Response to mitotane predicts outcome in patients with recurrent adrenal cortical carcinoma. Surgery. 2007;142:867-75; discussion 867-75 pubmed
    Adrenal cortical carcinoma (ACC) is a rare disease in which recurrence after surgery is common. Mitotane is the primary systemic treatment for recurrent ACC; data are limited regarding the impact of mitotane on recurrent ACC...
  11. Veytsman I, Nieman L, Fojo T. Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma. J Clin Oncol. 2009;27:4619-29 pubmed publisher
    ..Because chemotherapy benefits only a small percentage of patients, steroidogenesis inhibitors, including mitotane, ketoconazole, metyrapone, and etomidate, should be used singly or in combination even as chemotherapy is ..
  12. Attivi D, Ajana I, Astier A, Demoré B, Gibaud S. Development of microemulsion of mitotane for improvement of oral bioavailability. Drug Dev Ind Pharm. 2010;36:421-7 pubmed publisher
    b>Mitotane (o,p'-DDD) is considered to be the drug of choice in the treatment of nonresectable and metastasized adrenocortical carcinoma. However, mitotane has poor solubility in the gastrointestinal tract and very low bioavailability...
  13. Schteingart D. Adjuvant mitotane therapy of adrenal cancer - use and controversy. N Engl J Med. 2007;356:2415-8 pubmed
  14. Kamenicky P, Droumaguet C, Salenave S, Blanchard A, Jublanc C, Gautier J, et al. Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing's syndrome. J Clin Endocrinol Metab. 2011;96:2796-804 pubmed publisher
    b>Mitotane is highly effective in the long-term management of Cushing's syndrome but has a slow onset of action...
  15. Kroiss M, Quinkler M, Lutz W, Allolio B, Fassnacht M. Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma. Clin Endocrinol (Oxf). 2011;75:585-91 pubmed publisher
    b>Mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane, (o,p'-DDD)] is the only drug approved for the treatment for adrenocortical carcinoma (ACC) and has also been used for various forms of glucocorticoid excess...
  16. Nader N, Raverot G, Emptoz Bonneton A, Dechaud H, Bonnay M, Baudin E, et al. Mitotane has an estrogenic effect on sex hormone-binding globulin and corticosteroid-binding globulin in humans. J Clin Endocrinol Metab. 2006;91:2165-70 pubmed
    Side effects of mitotane (o,p'-DDD) have suggested estrogenic effects. The objective of the study was to explore o,p'-DDD potential estrogenic effect on SHBG and corticosteroid-binding globulin (CBG)...
  17. Baudry C, Coste J, Bou Khalil R, Silvera S, Guignat L, Guibourdenche J, et al. Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center. Eur J Endocrinol. 2012;167:473-81 pubmed publisher
    ..b>Mitotane is a potent anti-cortisolic drug but has been rarely investigated in the treatment of CD...
  18. Hahner S, Fassnacht M. Mitotane for adrenocortical carcinoma treatment. Curr Opin Investig Drugs. 2005;6:386-94 pubmed
    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 ..
  19. Menaa F, Menaa B. Development of mitotane lipid nanocarriers and enantiomers: two-in-one solution to efficiently treat adreno-cortical carcinoma. Curr Med Chem. 2012;19:5854-62 pubmed
    ..Indeed, radical tumor resection can lead to local or metastatic recurrence, and mitotane (Lysodren(®)), the only recognized adrenolytic drug, offers modest response rates, notably due to some of its ..
  20. Chortis V, Taylor A, Schneider P, Tomlinson J, Hughes B, O Neil D, et al. Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5?-reductase, explaining the need for personalized glucocorticoid and androgen replacement. J Clin Endocrinol Metab. 2013;98:161-71 pubmed publisher
    b>Mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane] is the first-line treatment for metastatic adrenocortical carcinoma (ACC) and is also regularly used in the adjuvant setting after presumed complete removal of the ..
  21. Khorram Manesh A, Ahlman H, Jansson S, Wangberg B, Nilsson O, Jakobsson C, et al. Adrenocortical carcinoma: surgery and mitotane for treatment and steroid profiles for follow-up. World J Surg. 1998;22:605-11; discussion 611-2 pubmed
    ..Twelve patients received mitotane with drug concentration measurements to deliver an effective, nontoxic dose...
  22. Haak H, Hermans J, van de Velde C, Lentjes E, Goslings B, Fleuren G, et al. Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer. 1994;69:947-51 pubmed
    b>Mitotane is considered to be the drug of choice for patients with inoperable, recurrent and metastatic adrenocortical carcinoma, although a favourable effect of this drug on survival has never been documented...
  23. Syme H, Scott Moncrieff J, Treadwell N, Thompson M, Snyder P, White M, et al. Hyperadrenocorticism associated with excessive sex hormone production by an adrenocortical tumor in two dogs. J Am Vet Med Assoc. 2001;219:1725-8, 1707-8 pubmed
    ..There was no improvement in clinical signs after treatment with mitotane in the female dog, which died 2 months after diagnosis...
  24. Gahan J, Shirodkar S, Gorin M, Salerno T, Ciancio G. Surgical resection of a virilizing adrenal mass with extensive tumor thrombus. Can J Urol. 2011;18:5735-8 pubmed
  25. Sparagana M, Ackerman L. Positive iodine-131 6 beta-iodomethyl-19-norcholesterol (NP-59) adrenal images can precede return of adrenocortical function after o,p' DDD treatment. Clin Nucl Med. 1988;13:348-51 pubmed
    ..Serial NP-59 adrenal images can anticipate the recurrence of Cushing's syndrome after adrenolytic therapy, thereby permitting early retreatment...
  26. Bapat A, Demeure M, Bussey K. A fly in the ointment: reassessing mitotane's role in the treatment of adrenocortical carcinoma. Pharmacogenomics. 2012;13:1207-9 pubmed publisher
  27. Freire D, Siqueira S, Zerbini M, Wajchenberg B, Correa Giannella M, Lucon A, et al. Development and internal validation of an adrenal cortical carcinoma prognostic score for predicting the risk of metastasis and local recurrence. Clin Endocrinol (Oxf). 2013;79:468-75 pubmed publisher
    ..Our model can be used to accurately estimate the risk of unfavourable outcomes in ACC patients. This score could be beneficial for both patient counselling and the identification of patients in whom adjuvant mitotane is justified.
  28. Chortis V, Johal N, Bancos I, Evans M, Skordilis K, Guest P, et al. Mitotane treatment in patients with metastatic testicular Leydig cell tumor associated with severe androgen excess. Eur J Endocrinol. 2018;178:K21-K27 pubmed publisher
    b>Mitotane (o,p'DDD) is established in the adjuvant and advanced-stage treatment of adrenocortical carcinoma and counteracts both tumor growth and tumor-related steroid production...
  29. Hamborg B, Frey H, Bøhmer T, Norman N. [Carcinoma of the adrenal cortex]. Tidsskr Nor Laegeforen. 1990;110:956-9 pubmed
    ..Median tumor weight was 487 g (118-2,085 g). Prognosis is difficult to predict. Median survival time after diagnosis was 34 months, but varied from three to 266 months. ..
  30. Borrelli D, Bergamini C, Borrelli A, Reddavide S, Lassig R, Valeri A. [Surgical strategy in the treatment of adrenal cortex cancer. Expanded and repeated interventions]. Ann Ital Chir. 2003;74:311-7 pubmed
    ..No significant difference was observed between Mitotane-treated and non-treated patients...
  31. Iihara M, Obara T. [Diagnosis and treatment for adrenocortical carcinoma]. Gan To Kagaku Ryoho. 2004;31:342-5 pubmed
    ..Surgical excision is the primary mode of therapy. Up to the present, mitotane (o, p'-DDD) treatment combined with chemotherapy has been the only palliative measure for patients with ..
  32. Lee J. Adjuvant mitotane in adrenocortical carcinoma. N Engl J Med. 2007;357:1258; author reply 1259 pubmed
  33. Carmona Bayonas A, Soler I, Gómez F, Billalabeitia E, Saura H, Tafalla M, et al. Tailored hormonal therapy in secretory adrenocortical cancer. Ann Oncol. 2007;18:1281 pubmed
  34. Alexandraki K, Kaltsas G, le Roux C, Fassnacht M, Ajodha S, Christ Crain M, et al. Assessment of serum-free cortisol levels in patients with adrenocortical carcinoma treated with mitotane: a pilot study. Clin Endocrinol (Oxf). 2010;72:305-11 pubmed publisher
    b>Mitotane treatment in adrenocortical carcinoma (ACC) results in unreliable measurement of serum total cortisol (TC) levels because of an elevation in corticosteroid-binding globulin (CBG)...
  35. Laus J, dos Santos C, Talieri I, Oriá A, Bechara G. Combined corneal lipid and calcium degeneration in a dog with hyperadrenocorticism: a case report. Vet Ophthalmol. 2002;5:61-4 pubmed
    ..The authors report a case of bilateral corneal lipid and calcium degeneration in a 7-year-old female Poodle with hyperadrenocorticism. The condition worsened with Lysodren therapy but responded to surgical excision. ..
  36. Katsumata N. [Virilizing adrenocortical tumor]. Nihon Rinsho. 2006;Suppl 1:705-7 pubmed
  37. Katsumata N. [Feminizing adrenocortical tumor]. Nihon Rinsho. 2006;Suppl 1:708-9 pubmed
  38. Webb C, Twedt D. Acute hepatopathy associated with mitotane administration in a dog. J Am Anim Hosp Assoc. 2006;42:298-301 pubmed
    An adult dog with a persistent elevation in alkaline phosphatase enzyme activity was started on mitotane for suspected hyperadrenocorticism. One month later, the dog was presented for intermittent anorexia and acute icterus...
  39. Helm J, McLauchlan G, Boden L, Frowde P, Collings A, Tebb A, et al. A comparison of factors that influence survival in dogs with adrenal-dependent hyperadrenocorticism treated with mitotane or trilostane. J Vet Intern Med. 2011;25:251-60 pubmed publisher
    ..4 centers over a period of 12 years that had been diagnosed with ADH and treated with either trilostane (22/37), mitotane (13/37), or both (2/37). Retrospective analysis of clinical records...
  40. Advani A, Vaikkakara S, Gill M, Arun C, Pearce S, Ball S, et al. Impact of standardised reporting in adrenocortical carcinoma: a single centre clinicopathological review. J Clin Pathol. 2008;61:939-44 pubmed publisher
    ..An elevated Ki-67 index is a feature of ACC, although it does not appear to predict individual patient survival. ..
  41. Jain S, Sadow P, Nose V, Dluhy R. A patient with ectopic cortisol production derived from malignant testicular masses. Nat Clin Pract Endocrinol Metab. 2008;4:695-700 pubmed publisher
    ..b>Mitotane and metyrapone were used to decrease cortisol production...
  42. Wandoloski M, Bussey K, Demeure M. Adrenocortical cancer. Surg Clin North Am. 2009;89:1255-67 pubmed publisher
    ..2% of all cancer deaths This article reviews the incidence, presentation, and pathology of ACC. Particular attention is paid to the molecular oncogenesis of this disease, and the surgical and therapeutic options available for its cure. ..
  43. Lin Y, Chen Y, Wu T, Chen L. Enhancement of dissolution rate of mitotane and warfarin prepared by using microemulsion systems. Colloids Surf B Biointerfaces. 2011;85:366-72 pubmed publisher
    ..Microemulsion systems were applied to micronize mitotane and warfarin by cooling method and solvent diffusion process...
  44. Grunenwald S, Caron P. [Adrenocortical carcinomas: therapeutic advances in 2011]. Ann Endocrinol (Paris). 2011;72 Suppl 1:S8-S14 pubmed publisher
    ..Very few adjuvant treatments are available and their efficacy is not fully proved. Adjuvant mitotane therapy increases the disease-free survival in the majority of patients after surgery but further studies are ..
  45. Thomas M, Lazartigues A, Banas D, Brun Bellut J, Feidt C. Organochlorine pesticides and polychlorinated biphenyls in sediments and fish from freshwater cultured fish ponds in different agricultural contexts in north-eastern France. Ecotoxicol Environ Saf. 2012;77:35-44 pubmed publisher
    ..64±0.15 ng g(-1) ww for carp. As for PCBs, the levels of ?PCBs ranged from 0.3 to 6.4 ng g(-1) ww in carp muscles and from 0.90 to 5.60 ng g(-1) ww in perch muscles. ..
  46. Lin C, Chang Y, Pu H. Mitotane exhibits dual effects on steroidogenic enzymes gene transcription under basal and cAMP-stimulating microenvironments in NCI-H295 cells. Toxicology. 2012;298:14-23 pubmed publisher
    ..The most common symptom of ACC is hypercortisolism (Cushing's syndrome), which has the highest mortality. Mitotane is used as a steroidogenesis inhibitor for Cushing's syndrome or as a chemical adrenalectomy drug for ACC...
  47. Shibata H. [Deoxycorticosterone-producing adrenal tumor]. Nihon Rinsho. 2006;Suppl 1:641-4 pubmed
  48. Behrend E, Weigand C, Whitley E, Refsal K, Young D, Kemppainen R. Corticosterone- and aldosterone-secreting adrenocortical tumor in a dog. J Am Vet Med Assoc. 2005;226:1662-6, 1659 pubmed
    ..Hyperaldosteronemia was detected as well. Treatment with mitotane was instituted and successful for a period of 4-months until the dog was euthanatized for neurologic problems ..
  49. Boushey R, Dackiw A. Adrenal cortical carcinoma. Curr Treat Options Oncol. 2001;2:355-64 pubmed
    ..Response to mitotane or chemotherapy is modest in patients with advanced disease...
  50. Berruti A, Fassnacht M, Baudin E, Hammer G, Haak H, Leboulleux S, et al. Adjuvant therapy in patients with adrenocortical carcinoma: a position of an international panel. J Clin Oncol. 2010;28:e401-2; author reply e403 pubmed publisher
  51. Mathivon L, Carel J, Coutant R, Derome P, Adamsbaum C, Bougneres P, et al. [Cushing disease in children and in adolescents. Therapeutic results]. Arch Pediatr. 1997;4:521-8 pubmed
    ..Trans-sphenoidal surgery is currently the treatment of choice for Cushing's disease in children...
  52. Terzolo M, Baudin A, Ardito A, Kroiss M, Leboulleux S, Daffara F, et al. Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection. Eur J Endocrinol. 2013;169:263-70 pubmed publisher
    b>Mitotane plasma concentrations ? 14 mg/l have been shown to predict tumor response and better survival in patients with advanced adrenocortical carcinoma (ACC)...
  53. Fassnacht M, Kroiss M, Allolio B. Update in adrenocortical carcinoma. J Clin Endocrinol Metab. 2013;98:4551-64 pubmed publisher
    ..Even after complete surgery, recurrence is frequent and adjuvant mitotane treatment improves outcome, but uncertainty exists as to whether all patients benefit from this therapy...