The Efficacy of Mitotane in Human Primary Adrenocortical Carcinoma Cultures

CONTEXT: Patients with adrenocortical carcinoma (ACC) often fail mitotane treatment and deal with severe toxicity, marking the relevance of predictive parameters for treatment outcome. OBJECTIVE: Determine the effects of mitotane in primary ACC cultures, and correlate sensitivity with patient and tumor characteristics. METHODS: In 32 primary ACC cultures, the effects of mitotane on cell growth and cortisol production were determined. RRM1, SOAT1, and CYP2W1 expression were assessed using reverse transcription-polymerase chain reaction and immunohistochemistry. RESULTS: The median percentage cell amount inhibition in primary ACC cultures at 50 µM mitotane was 57%. Seven patients were classified as nonresponders, 14 as partial responders, and 11 as responders. The mean median effective concentration (EC(50)) value of mitotane for inhibition of cell amount in responders was 14.2 µM (95% CI, 11.3–17.9), in partial responders 41.6 µM (95% CI, 33.5–51.8), and could not be calculated in nonresponders. The percentage cortisol-producing ACC was 14%, 43%, and 73% for nonresponders, partial responders, and responders (P = 0.068). Mitotane inhibited cortisol production with a mean EC(50) of 1.4 µM (95% CI, 0.9–2.1), which was considerably lower than the EC(50) on cell growth. RRM1, SOAT1, and CYP2W1 expression levels were not predictive for mitotane sensitivity in vitro. CONCLUSION: Direct antitumor effects of mitotane on human primary ACC cultures are highly variable between patients, reflecting heterogeneous responses in patients. Cortisol was inhibited at lower concentrations, compared with its effect on cell amount. Cortisol secretion by ACC might be associated with enhanced mitotane sensitivity due to increased direct antitumor effects of mitotane.