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Efficacy of temozolomide combined with capecitabine (CAPTEM) on refractory prolactinomas as assessed using an ex vivo 3D spheroid assay

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Abstract

Purpose

Refractory prolactinomas resistant to dopamine agonists (DAs) pose a clinical challenge. Temozolomide (TMZ) is a recommended treatment option, but its effects are difficult to predict, and the alternatives are limited. Recent reports suggested that TMZ combined with capecitabine (CAPTEM) can be effective for the treatment of aggressive pituitary tumors. This study sought to evaluate the effect of TMZ in an ex vivo three-dimensional (3D) spheroid culture assay and determine if this assay could be used to predict the therapeutic effect of CAPTEM in actual refractory prolactinomas.

Methods

Surgically resected tumor tissues from two patients with refractory prolactinoma were cultured as 3D spheroids. The effects of TMZ were assessed based on its suppression of cell viability and reduction of prolactin (PRL) levels.

Results

In Case 1, the 3D culture assay showed no effect of TMZ on cell viability or PRL suppression. Clinically, TMZ treatment did not reduce PRL levels (8870→8274 ng/mL) and the tumor progression. However, CAPTEM partially reduced PRL levels (9070→4046 ng/mL) and suppressed the tumor growth. In Case 2, TMZ in the 3D culture assay showed a 50% reduction of cell viability and 40% reduction of PRL levels. Clinically, CAPTEM was highly effective, with a considerable reduction in PRL level (17,500→210 ng/mL), and MRI showed almost no residual tumor.

Conclusions

This is the first report to describe the effects of CAPTEM treatment on refractory prolactinomas. The ex vivo 3D spheroid culture assay reliably predicted TMZ sensitivity and informed the selection between TMZ or CAPTEM treatment for refractory prolactinomas.

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Acknowledgements

We would like to thank Drs. Hideki Shiramizu, Haruko Yoshimoto, Masataka Kato, Nobuhiro Miki, Masami Ono for discussion.

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Authors and Affiliations

  1. Department of Neurosurgery, Moriyama Memorial Hospital, 134-0081, Tokyo, Japan

    Atsushi Ishida

  2. Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 650-0017, Kobe, Japan

    Hiroki Shichi & Wataru Ogawa

  3. Division of Diabetes and Endocrinology, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, 650-0017, Kobe, Japan

    Hidenori Fukuoka

  4. Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 173-0015, Tokyo, Japan

    Naoko Inoshita

  5. Hypothalamic & Pituitary Center, Moriyama Neurological Center Hospital, 134-0088, Tokyo, Japan

    Shozo Yamada

Authors
  1. Atsushi Ishida
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  2. Hiroki Shichi
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  3. Hidenori Fukuoka
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  4. Naoko Inoshita
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  5. Wataru Ogawa
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  6. Shozo Yamada
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Corresponding author

Correspondence to Hidenori Fukuoka.

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Conflict of interest

The authors have no multiplicity of interests to disclose.

Ethical approval

Study protocols were approved by the Moriyama Memorial Hospital Institutional Review Board. Informed consent was obtained from the patients. 3D spheroid culture experiments were conducted in compliance with the protocol that was reviewed and approved by the Research Ethics Committee of Kobe University Hospital (IRB#1363).

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Ishida, A., Shichi, H., Fukuoka, H. et al. Efficacy of temozolomide combined with capecitabine (CAPTEM) on refractory prolactinomas as assessed using an ex vivo 3D spheroid assay. Pituitary 25, 238–245 (2022). https://doi.org/10.1007/s11102-021-01192-x

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