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The Efficacy of Mitotane in Human Primary Adrenocortical Carcinoma Cultures
Peter M van Koetsveld1, Sara G Creemers1, Fadime Dogan1
1Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
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 (EC50) 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 EC50 of 1.4 µM (95% CI, 0.9-2.1), which was considerably lower than the EC50 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.
Insights
Mitotane treatment for adrenocortical carcinoma (ACC) shows variable patient responses. Cortisol production may enhance mitotane
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Adrenocortical carcinoma (ACC) treatment often involves mitotane, but patient responses are frequently suboptimal, with significant toxicity.
- Identifying predictive markers for mitotane efficacy is crucial for improving treatment outcomes in ACC patients.
Purpose of the Study:
- To investigate the direct effects of mitotane on primary ACC cell cultures.
- To correlate mitotane sensitivity in vitro with patient and tumor characteristics, including gene expression and cortisol production.
Main Methods:
- Primary ACC cell cultures were established from 32 patients.
- Mitotane's impact on cell growth and cortisol production was assessed.
- Expression of RRM1, SOAT1, and CYP2W1 was analyzed via RT-PCR and immunohistochemistry.
Main Results:
- Mitotane demonstrated variable inhibition of ACC cell growth (median 57% at 50 µM).
- Cortisol production was inhibited at significantly lower mitotane concentrations (EC50 1.4 µM) than cell growth (EC50 14.2 µM in responders).
- RRM1, SOAT1, and CYP2W1 expression levels did not predict in vitro mitotane sensitivity.
Conclusions:
- Direct antitumor effects of mitotane on ACC are patient-specific, reflecting clinical heterogeneity.
- Cortisol secretion may be linked to increased mitotane sensitivity, potentially enhancing its direct antitumor effects.
- Further research is needed to elucidate mechanisms underlying variable mitotane response in ACC.
