Therapeutic concentrations of mitotane (o,p'-DDD) inhibit thyrotroph cell viability and TSH expression and secretion in a mouse cell line model

Zatelli, Maria Chiara; Gentilin, Erica; Daffara, Fulvia; Tagliati, Federico; Reimondo, Giuseppe; Carandina, Gianni; Ambrosio, Maria Rosaria; Terzolo, Massimo; degli Uberti, Ettore C.

doi:10.1210/en.2009-1404

Cited by 57Thyroid Disorders and TreatmentsAdrenal Hormones and DisordersPituitary Gland Disorders and Treatments

Therapeutic concentrations of mitotane (o,p'-DDD) inhibit thyrotroph cell viability and TSH expression and secretion in a mouse cell line model

Zatelli, Maria Chiara, Gentilin, Erica, Daffara, Fulvia, Tagliati, Federico, Reimondo, Giuseppe, Carandina, Gianni, Ambrosio, Maria Rosaria, Terzolo, Massimo +1 more·2010·Endocrinology

DOI 10.1210/en.2009-1404

Open this paper in CoChat — free account

Abstract

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. We investigated whether increasing concentrations of mitotane in the therapeutic range might interfere with thyroid hormone assays and evaluated the effects of mitotane on a mouse TSH-producing pituitary cell line. TSH, free T(4), and free T(3) levels do not significantly change in sera from hypo-, hyper-, or euthyroid patients after addition of mitotane at concentrations in the therapeutic window. In the mouse TalphaT1 cell line, mitotane inhibits both TSH expression and secretion, blocks TSH response to TRH, and reduces cell viability, inducing apoptosis at concentrations in the therapeutic window. TRH is not capable of rescuing TalphaT1 cells from the inhibitory effects of mitotane on TSH expression and secretion, which appear after short time treatment and persist over time. Our results demonstrate that mitotane does not interfere with thyroid hormone laboratory tests but directly reduces both secretory activity and cell viability on pituitary TSH-secreting mouse cells. These data represent a possible explanation of the biochemical picture consistent with central hypothyroidism in patients undergoing mitotane therapy and open new perspectives on the direct pituitary effects of this drug.

Integrity signals

Registry

Crossref · 10.1210/en.2009-1404

Cites

35 of 35 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Changes in thyroid function are due to partial central hypothyroidism, backed by experiments in cell lines where mitotane directly induces apoptosis in thyrotrope cells.
“One interpretation is that the changes are due to partial central hypothyroidism. This is further backed up by experiments in cell lines, where mitotane directly induces apoptosis in thyrotrope cells (300).”
From Adrenocortical carcinoma (2014) · cites this paper as [300]
The decrease in free T4 is not a laboratory artifact because mitotane does not interfere with thyroid hormone measurements.
“It has been determined that this is not a laboratory artifact because mitotane does not interfere with thyroid hormone measurements (300).”
From Adrenocortical carcinoma (2014) · cites this paper as [300]

A new mathematical model for relative quantification in real-time RT-PCR
Pfaffl, M. W. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.9.e45 · Cited by 34,610 · see citing works
Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes
Vandesompele, J., De Preter, K., Pattyn, F., Poppe, B., Van Roy, N., De Paepe, A., & Speleman, F. (2002) · Genome Biology · doi:10.1186/gb-2002-3-7-research0034 · Cited by 20,038 · see citing works
Glycoprotein Hormones: Structure and Function
Pierce, J. G., & Parsons, T. F. (1981) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.50.070181.002341 · Cited by 2,306 · see citing works
Adrenocortical Carcinoma: Clinical Update
Allolio, B., & Fassnacht, M. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-2639 · Cited by 775 · see citing works
Adjuvant Mitotane Treatment for Adrenocortical Carcinoma
Terzolo, M., Angeli, A., Faßnacht, M., Daffara, F., Tauchmanovà, L., Conton, P. A., Rossetto, R., Buci, L., Sperone, P., Grossrubatscher, E. M., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa063360 · Cited by 759 · see citing works
Self-citation
Management of patients with adrenal cancer: recommendations of an international consensus conference
Schteingart, D. E., Doherty, G. M., Gauger, P. G., Giordano, T. J., Hammer, G. D., Korobkin, M., & Worden, F. P. (2005) · Endocrine Related Cancer · doi:10.1677/erc.1.01029 · Cited by 421 · see citing works
An eleven-year experience with adrenocortical carcinoma.
Pommier, R. F., & Brennan, M. F. (1992) · PubMed · Cited by 332 · see citing works
Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients
Haak, H. R., Hermans, J., van de Velde, C., Lentjes, E. G. W. M., Goslings, B. M., Fleuren, G. J., & Krans, H. (1994) · British Journal of Cancer · doi:10.1038/bjc.1994.183 · Cited by 329 · see citing works
Adrenocortical cancer: pathophysiology and clinical management
Libé, R., Fratticci, A., & Bertherat, J. Y. (2007) · Endocrine Related Cancer · doi:10.1677/erc.1.01130 · Cited by 271 · see citing works
CHEMOTHERAPY OF ADRENOCORTICAL CANCER WITH o,p′DDD
Bergenstal, D. M., Hertz, R., Lipsett, M. B., & Moy, R. H. (1960) · Annals of Internal Medicine · doi:10.7326/0003-4819-53-4-672 · Cited by 230 · see citing works
Thyroid-Stimulating Hormone: Biosynthesis, Cell Biology, and Bioactivity
Magner, J. A. (1990) · Endocrine Reviews · doi:10.1210/edrv-11-2-354 · Cited by 179 · see citing works
Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly
Daffara, F., De Francia, S., Reimondo, G., Zaggia, B., Aroasio, E., Porpiglia, F., Volante, M., Termine, A., Di Carlo, F., Dogliotti, L., et al. (2008) · Endocrine Related Cancer · doi:10.1677/erc-08-0103 · Cited by 167 · see citing works
Self-citation
Molecular Biology of Thyrotropin
Shupnik, M. A., Ridgway, E. C., & Chin, W. W. (1989) · Endocrine Reviews · doi:10.1210/edrv-10-4-459 · Cited by 148 · see citing works
Low-Dose Monitored Mitotane Treatment Achieves the Therapeutic Range with Manageable Side Effects in Patients with Adrenocortical Cancer 1
Terzolo, M., Pia, A. R., Berruti, A., Osella, G., Alı̀, A., Carbone, V., Testa, E., Dogliotti, L., & Angeli, A. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.6.6619 · Cited by 116 · see citing works
Self-citation
Somatostatin Receptor Subtype 1 Selective Activation in Human Growth Hormone (GH)- and Prolactin (PRL)-Secreting Pituitary Adenomas: Effects on Cell Viability, GH, and PRL Secretion
Zatelli, M. C., Piccin, D., Tagliati, F., et al. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-021825 · Cited by 93 · see citing works
Self-citation
Mitotane Has an Estrogenic Effect on Sex Hormone-Binding Globulin and Corticosteroid-Binding Globulin in Humans
Nader, N., Raverot, G., Emptoz-Bonneton, A., Déchaud, H., Bonnay, M., Baudin, E., & Pugeat, M. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-2157 · Cited by 89 · see citing works
Mitotane increases the blood levels of hormone-binding proteins
van Seters, A. P., & Moolenaar, A. J. (1991) · European Journal of Endocrinology · doi:10.1530/acta.0.1240526 · Cited by 82 · see citing works
Somatostatin Receptor Subtypes 2 and 5 Differentially Affect Proliferationin Vitroof the Human Medullary Thyroid Carcinoma Cell Line TT1
Zatelli, M. C., Tagliati, F., Taylor, J. E., et al. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.5.7489 · Cited by 77 · see citing works
Self-citation
o,p′-DDD (mitotane) therapy of adrenal cortical carcinoma. Observations on drug dosage, toxicity, and steroid replacement
Hogan, T. F., Citrin, D. L., Johnson, B. M., Nakamura, S., Davis, T. E., & Borden, E. C. (1978) · Cancer · doi:10.1002/1097-0142(197811)42:5 · Cited by 72 · see citing works
Blood levels of o,p′-DDD following administration in various vehicles after a single dose and during long-term treatment
Moolenaar, A. J., van Slooten, H., van Seters, A. P., & Smeenk, D. (1981) · Cancer Chemotherapy and Pharmacology · doi:10.1007/bf00258213 · Cited by 72 · see citing works
How medications affect thyroid function
Dong, B. J. (2000) · Western Journal of Medicine · doi:10.1136/ewjm.172.2.102 · Cited by 70 · see citing works
Somatostatin Receptor Subtypes 2 and 5 Differentially Affect Proliferation in Vitro of the Human Medullary Thyroid Carcinoma Cell Line TT
Zatelli, M. C. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.5.2161 · Cited by 68 · see citing works
Self-citation
Effect of o,p'-DDD and Similar Compounds on Thyroxine Binding Globulin
Marshall, J. S., & TOMPKIN, L. S. (1968) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-28-3-386 · Cited by 60 · see citing works
Somatostatin receptor subtype 1-selective activation reduces cell growth and calcitonin secretion in a human medullary thyroid carcinoma cell line
Zatelli, M. C., Tagliati, F., Piccin, D., Taylor, J. E., Culler, M. D., Bondanelli, M., & Uberti, E. C. D. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)02307-0 · Cited by 57 · see citing works
Self-citation
Mitotane increases the radiotherapy inhibitory effect and induces G2-arrest in combined treatment on both H295R and SW13 adrenocortical cell lines
Cerquetti, L., Bucci, B., Marchese, R., Misiti, S., Paula, U. D., Miceli, R., Muleti, A., Amendola, D., Piergrossi, P., Brunetti, E., et al. (2008) · Endocrine Related Cancer · doi:10.1677/erc.1.1315 · Cited by 55 · see citing works
Complexing of DDT and o,p'DDD with adrenal cytochrome P-450 hydroxylating systems
Young, R. B., Bryson, M. J., Sweat, M. L., et al. (1973) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(73)90033-2 · Cited by 52 · see citing works
Adjuvant Mitotane in Adrenocortical Carcinoma
Bertherat, J. Y., Coste, J., & BERTAGNA, X. Y. (2007) · New England Journal of Medicine · doi:10.1056/nejmc076267 · Cited by 50 · see citing works
Modulation of proteomic profile in H295R adrenocortical cell line induced by mitotane
Stigliano, A., Cerquetti, L., Borro, M., et al. (2008) · Endocrine Related Cancer · doi:10.1677/erc-07-0003 · Cited by 50 · see citing works
The Thyrotropin β-Subunit Gene Is Repressed by Thyroid Hormone in a Novel Thyrotrope Cell Line, Mouse TαT1 Cells**This work was supported by NIH Research Grants R01-HD-20377 and HD-12303 (to P.L.M.) and R01-DK-36843 (to E.C.R.); fellowships from the Spanish Ministry of Education and Science and Fundacion Jaime del Amo, Universidad Complutense de Madrid, Spain (to B.Y.); and a Ford Foundation Fellowship, the President’s Fellowship of the University of California, and NIH National Research Scientist Award Fellowship DK-09145 (to E.T.A.).
Yusta, B., Alarid, E. T., Gordon, D. F., Ridgway, E. C., & Mellon, P. L. (1998) · Endocrinology · doi:10.1210/endo.139.11.6283 · Cited by 46 · see citing works
Reminders of Drug Effects on Laboratory Test Results
Kailajärvi, M., Takala, T. I., Grönroos, P. E., Tryding, N., Viikari, J. S. A., Irjala, K. M. A., & Forsström, J. (2000) · Clinical Chemistry · doi:10.1093/clinchem/46.9.1395 · Cited by 32 · see citing works
A new simple HPLC method for measuring mitotane and its two principal metabolites
Francia, S. D., Pirro, E., Zappia, F., Martino, F., Sprio, A. E., Daffara, F., Terzolo, M., Berruti, A., Carlo, F. D., & Ghezzo, F. (2006) · Journal of Chromatography B · doi:10.1016/j.jchromb.2006.04.005 · Cited by 29 · see citing works
Self-citation
Cytotoxic activity of 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane (mitotane) and its analogs on feminizing adrenal neoplastic cells in culture.
Fang, V. S. (1979) · PubMed · Cited by 24 · see citing works
Activation of the Thyroid-Stimulating Hormone β-Subunit Gene by LIM Homeodomain Transcription Factor Lhx2
Kim, K. K., Song, S. B., Kang, K. I., Rhee, M., & Kim, K. E. (2007) · Endocrinology · doi:10.1210/en.2006-1088 · Cited by 23 · see citing works
Urinary calcium excretion in the monitoring of bone metastases from prostatic carcinoma
Francini, G., Petrioli, R., Gonnelli, S., Correale, P., Pozzessere, D., Marsili, S., Montagnani, A., Lucani, B., Rossi, S., Monaco, R. D., et al. (2001) · Cancer · doi:10.1002/1097-0142(20010915)92:6 · Cited by 15 · see citing works
Effect of o,p'-DDD and Li+ on apoptotic DNA fragmentation in conventionally normal and tumour tissues of human adrenal cortex.
Pushkarev, V. M., Tronko, M. D., Kostyuchenko, N., et al. (2008) · PubMed · Cited by 9 · see citing works

Flagged first, then by citations

Sorted by citations

Adrenocortical carcinoma
Else, T., Kim, A. C., Sabolch, A., Raymond, V. M., Kandathil, A., Caoili, E. M., Jolly, S., Miller, B. S., Giordano, T. J., & Hammer, G. D. (2014) · Endocrine Reviews · doi:10.1210/er.2013-1029 · Cited by 892 · see citing works
Thyroid Dysfunction as an Unintended Side Effect of Anticancer Drugs
Torino, F., Barnabei, A., Paragliola, R., Baldelli, R., Appetecchia, M., & Corsello, S. M. (2013) · Thyroid® · doi:10.1089/thy.2013.0241 · Cited by 117 · see citing works
Central hypothyroidism and its role for cardiovascular risk factors in hypopituitary patients
Feldt-Rasmussen, U., & Klose, M. (2016) · Endocrine · doi:10.1007/s12020-016-1047-x · Cited by 43 · see citing works
Mitotane treatment in patients with adrenocortical cancer causes central hypothyroidism
Russo, M., Scollo, C., Pellegriti, G., Cotta, O. R., Squatrito, S., Frasca, F., Cannavò, S., & Gullo, D. (2016) · Clinical Endocrinology · doi:10.1111/cen.12868 · Cited by 36 · see citing works
Central hypothyroidism in adults: better understanding for better care
Grunenwald, S., & Caron, P. (2015) · Pituitary · doi:10.1007/s11102-014-0559-8 · Cited by 35 · see citing works
Less known aspects of central hypothyroidism: Part 1- Acquired etiologies
Benvenga, S., Klose, M., Vita, R., & Feldt-Rasmussen, U. (2018) · Journal of Clinical & Translational Endocrinology · doi:10.1016/j.jcte.2018.09.003 · Cited by 19 · see citing works
Interactions between hypothalamic pituitary thyroid axis and other pituitary dysfunctions
Feldt-Rasmussen, U., Klose, M., & Benvenga, S. (2018) · Endocrine · doi:10.1007/s12020-018-1738-6 · Cited by 12 · see citing works

Eastern Cooperative Oncology Group study 1879: mitotane and adriamycin in patients with advanced adrenocortical carcinoma.
Decker, R. A., Elson, P. J., Hogan, T. F., Citrin, D. L., Westring, D. W., Banerjee, T. K., Gilchrist, K. W., & Horton, J. (1991) · PubMed · Cited by 77 · see citing works
Changes in neoplastic cell features and sensitivity to mitotane during mitotane-induced remission in a patient with recurrent, metastatic adrenocortical carcinoma.
Seki, M., Nomura, K., Hirohara, D., Kanazawa, M., Sawada, T., Takasaki, K., & Demura, H. (1999) · Endocrine Related Cancer · doi:10.1677/erc.0.0060529 · Cited by 9 · see citing works
Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients
Haak, H. R., Hermans, J., van de Velde, C., Lentjes, E. G. W. M., Goslings, B. M., Fleuren, G. J., & Krans, H. (1994) · British Journal of Cancer · doi:10.1038/bjc.1994.183 · Cited by 329 · see citing works
Circannual variation of mitotane and its metabolites plasma levels in patients with adrenocortical carcinoma
Cusato, J., Francia, S. D., Allegra, S., Carrella, S., Pirro, E., Piccione, F. M., Martino, F., Ferrero, A., Daffara, F., Terzolo, M., et al. (2017) · Journal of Pharmacy and Pharmacology · doi:10.1111/jphp.12798 · Cited by 9 · see citing works
Self-citation
Mitotane for adrenocortical carcinoma treatment.
Hahner, S., & Faßnacht, M. (2005) · PubMed · Cited by 153 · see citing works

Authors: Zatelli, M. C., Gentilin, E., Daffara, F., Tagliati, F., Reimondo, G., Carandina, G., Ambrosio, M. R., Terzolo, M., & degli Uberti, E. C.
Affiliations: University of Ferrara (IT)
Arcispedale Sant'Anna (IT)
Ospedale San Luigi Gonzaga (IT)
Section of Endocrinology (M.C.Z., E.G., F.T., M.R.A., E.C.d.U.), Santa Anna Hospital, 44121 Ferrara, Italy
ORCID: Zatelli, Maria Chiara
Gentilin, Erica
Reimondo, Giuseppe
Ambrosio, Maria Rosaria
Terzolo, Massimo
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2010-04-14
Volume: 151
Issue: 6
Pages: 2453-2461
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2009-1404
OpenAlex: W2134264575
Cited by: 57
References: 35
Citations by year: 2026: 2 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 4 · 2017: 2 · 2016: 3 · 2015: 7 · 2014: 8 · 2013: 9 · 2012: 2
FWCI: 3.12
Type: journal article
Language: en
Open access: closed
Locations: Endocrinology (publishedVersion)
PubMed (publishedVersion)
Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
Padua Research Archive (University of Padova) (submittedVersion)
Funders: Associazione Italiana per la Ricerca sul Cancro
Università degli Studi di Ferrara
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
Keywords: mitotane, central hypothyroidism, thyroid-stimulating hormone, TSH secretion, pituitary cells, thyrotropin-releasing hormone, apoptosis, cell viability, thyroid function tests, adverse drug reactions, thyroid hormone assay
MeSH terms: Animals, Cell Survival, Enzyme-Linked Immunosorbent Assay, Humans, Mitotane, Thyrotropin, Thyrotropin-Releasing Hormone, Thyroxine, Triiodothyronine, Antineoplastic Agents, Hormonal, Reverse Transcriptase Polymerase Chain Reaction, Mice, Thyrotrophs

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Therapeutic concentrations of mitotane (o,p'-DDD) inhibit thyrotroph cell viability and TSH expression and secretion in a mouse cell line model

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks