The effect of 2, 2-Bis (2-chlorophenyl-4-chlorophenyl)-1, 1-dighloroethane (o, p'-DDD) on the metabolism of infused cortisol-7-3H

Southren, A. Louis; Tochimoto, Satoru; Isurugi, Koichiro; Gordon, Gary G.; Krikun, Eliseo; Stypulkowski, Walter

doi:10.1016/0039-128x(66)90132-2

Cited by 23 publications

(13 citation statements)

References 6 publications

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“…None of these were initially apparent during analysis by our standard method, which involves a wash step in which the sample is partitioned between water and ethyl acetate. Omitting this step led to much higher recoveries, showing that the steroids were being lost in the water phase and confirming early observations (10) that a large proportion of cortisol metabolites is found in a polar fraction after mitotane treatment.…”

Section: Resultssupporting

confidence: 85%

“…However, evidence for decrease in cortisol secretion due to mitotane as a contributor to increased hydrocortisone dose requirement is lacking. In a single patient with secondary Cushing's syndrome, short-term treatment did not diminish cortisol metabolic clearance rate nor secretion rate (10). During long-term administration to six patients with various clinical disorders, cortisol secretion rate was diminished in two, did not change in two and increased in two (11).…”

Section: Discussionmentioning

confidence: 76%

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Effects of mitotane treatment on human steroid metabolism: implications for patient management

Ghataore¹,

Chakraborti²,

Aylwin³

et al. 2012

Endocrine Connections

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Mitotane (o,p'-DDD), an oral adrenolytic agent for treatment of advanced adrenocortical carcinoma (ACC), is reported to inhibit cortisol biosynthesis in vitro and enhance production from exogenous cortisol of urinary 6β-hydroxycortisol and unidentified polar unconjugated metabolites. We examined urinary steroid profiles by gas chromatography–mass spectrometry of patients with histologically confirmed ACC following surgery, receiving a) hydrocortisone alone (three males and three females) and b) mitotane and hydrocortisone (six males and 11 females). Samples were collected after plasma mitotane had reached the therapeutic range of 14–20 mg/l. Increased excretion of polar unconjugated steroids during mitotane treatment was confirmed, with 6β-hydroxycortisol and 6β-hydroxy-20-dihydrocortisols predominating. The proportion of additionally hydroxylated metabolites was <2% in untreated controls and 52, 35–52% (mean, range) in the mitotane plus hydrocortisone group. Ratios of 5α-/5β- and 20β-/20α-metabolites of administered cortisol were decreased 50-, 15-fold, and 14-, 8-fold respectively (males, females – mean values) but with no change in metabolite ratios that reflect oxidoreduction at C11 or C20. Patterns of decrease in 5α- relative to 5β-reduced metabolites were similar to those of patients with 5α-reductase 2 deficiency or on treatment with the 5α-reductase 2 inhibitor finasteride but different from those of patients on dutasteride, indicating specific inhibition of 5α-reductase 2. We conclude that mitotane causes consistent changes in cortisol catabolism, most of which have not been previously recognised. These need not interfere with early detection of ACC recurrence. Induction of 6β-hydroxylation offers an explanation for a reported decrease in cortisol bioavailability. Mitotane also has potential as a unique steroid metabolic probe for 20β-reduction.

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Section: Resultssupporting

confidence: 85%

Section: Discussionmentioning

confidence: 76%

Effects of mitotane treatment on human steroid metabolism: implications for patient management

Ghataore¹,

Chakraborti²,

Aylwin³

et al. 2012

Endocrine Connections

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“…Mitotane is derived from the insecticide dichlorodiphenyltrichloroethane (DDT) and is administered orally in tablets in two to three daily doses. The drug exerts an anti-neoplastic effect on ACC tissue and in addition inhibits cortisol synthesis, which is beneficial in patients with Cushing's syndrome (Southren et al 1966, Fukushima et al 1971, Touitou et al 1978, Ghataore et al 2012. The antineoplastic effect is correlated with the plasma level of mitotane.…”

Section: Mitotanementioning

confidence: 99%

Developing treatment for adrenocortical carcinoma

Kerkhofs¹,

Ettaieb²,

Hermsen³

et al. 2015

Endocrine-Related Cancer

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Cancer of the adrenal cortex (ACC) is a rare endocrine malignancy with limited treatment options. Patients typically present with autonomous hormonal overproduction and/or a large abdominal mass. Hormonal assays and medical imaging can be diagnostic, but urinary steroid profiling might be a more sensitive technique to assess malignancy in adrenal tumours. The stage of the disease at diagnosis is the most important prognostic factor. The current staging system needs refinement, especially to separate aggressive from indolent disease in stage IV patients and to select patients who need adjuvant treatment after complete surgical resection. Regarding the latter, assessing the proliferation index Ki-67 seems the best tool currently available. Genomic profiling is expected to become of clinical relevance in the future. Medical therapy is centred on the adrenolytic drug mitotane, which carries considerable toxicity and is not easy to manage. Its tolerability and long plasma level build-up phase may be improved by therapeutic drug monitoring based on pharmacokinetic modelling and intensive counselling of patients. Current chemotherapy regimens can offer disease stabilization in about 50% of patients, but an objective response should be expected in !25%. Research on targeted therapy and immunotherapy is difficult in this rare disease with often heavily pre-treated patients and has not yet been successful. Quality of care should be ensured by treating patients in centres with established experience in multidisciplinary oncologic care, who adhere to prevailing guidelines and state-of-the-art in diagnostic and treatment concepts. International collaboration in fundamental research and clinical trials is the key to further elucidate the pathogenesis and to improve patient care.

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“…Adverse reactions are common mainly to the gastrointestinal, central nervous system, and derma, but nontolerable toxic events are rare when the plasma concentration is less than 15 g/ml. Adrenocortical glands become necrotic and 17-hydroxycorticosteroid secretion is inhibited [9,10]. DDD's exact antitumour molecular mechanism is unknown and it is still unclear whether it is induced by DDD itself or one of its metabolites such as DDE or DDA following ␣-and ␤-hydroxylation, respectively ( Fig.…”

Section: Introductionmentioning

confidence: 97%

A new simple HPLC method for measuring mitotane and its two principal metabolites

Francia

Pirro

Zappia³

et al. 2006

Journal of Chromatography B

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The effect of 2, 2-Bis (2-chlorophenyl-4-chlorophenyl)-1, 1-dighloroethane (o, p'-DDD) on the metabolism of infused cortisol-7-3H

Cited by 23 publications

References 6 publications

Effects of mitotane treatment on human steroid metabolism: implications for patient management

Effects of mitotane treatment on human steroid metabolism: implications for patient management

Developing treatment for adrenocortical carcinoma

A new simple HPLC method for measuring mitotane and its two principal metabolites

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