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

Abstract

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.

Rak kory nadnercza (ACC) — przegląd piśmiennictwa i doświadczenia własne

“…If USP normalises after radical tumour removal, it can subsequently serve as a tool in the early detection of recurrence of disease if the specific markers for a particular patient recurred. Interestingly, even though mitotane influences USP pattern, it still can be used for early detection of the recurrence of disease [19].…”

“…Mitotane has a specific cytotoxic effect on mitochondria of adrenal cortical cells. It has been reported to inhibit cortisol biosynthesis in vitro and enhance production form exogenous cortisol of urinary 6β-hydroxycortisol and unidentified polar unconjugated metabolites [46].…”

“…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 [46].…”

“…Jeśli wyniki USP normalizują się tuż po zabiegu radykalnego usunięcia guza, metoda ta może posłużyć jako narzędzie diagnostyczne we wczesnym wykrywaniu wznowy choroby nowotworowej. Interesujące jest to, że mimo wpływu mitotanu na test USP, nadal może on być wykorzystywany do wczesnego wykrywania nawrotu choroby [19].…”

“…Mitotan wykazuje specyficzne działanie cytotoksyczne wobec mitochondriów komó-rek kory nadnerczy. Z doniesień wiadomo, że hamuje on biosyntezę kortyzolu in vitro oraz wzmacnia produkcję wydalanego z moczem 6β-hydroksykortyzolu oraz niezwiązanych polarnie metabolitów powstających z egzogennego kortyzolu [46]. Z ostatnich badań przedklinicznych wiadomo, że mitotan redukuje przeżywal-ność komórek NCIH295R (ludzka linia komórek ACC) poprzez indukcję apoptozy spowodowaną zwiększe-niem aktywności kaspazy 3 oraz kaspazy 7.…”