Department of Neurosurgery, Moriyama Memorial Hospital, 134-0081, Tokyo, Japan.
Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 650-0017, Kobe, Japan.
Pituitary. 2022 Apr;25(2):238-245. doi: 10.1007/s11102-021-01192-x. Epub 2021 Nov 13.
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.
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.
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.
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.
对多巴胺激动剂（DAs）耐药的难治性泌乳素瘤是临床治疗的难点。替莫唑胺（TMZ）是一种推荐的治疗选择，但疗效难以预测，而且选择有限。最近的报告表明，TMZ 联合卡培他滨（CAPTEM）可有效治疗侵袭性垂体肿瘤。本研究旨在评估 TMZ 在体外三维（3D）球体培养测定中的作用，并确定该测定是否可用于预测 CAPETM 在实际难治性泌乳素瘤中的治疗效果。
对两名难治性泌乳素瘤患者的手术切除肿瘤组织进行 3D 球体培养。根据 TMZ 对细胞活力的抑制作用和催乳素（PRL）水平的降低来评估 TMZ 的作用。
在病例 1 中，3D 培养测定显示 TMZ 对细胞活力或 PRL 抑制无作用。临床上，TMZ 治疗并未降低 PRL 水平（8870→8274ng/mL）和肿瘤进展。然而，CAPTEM 部分降低了 PRL 水平（9070→4046ng/mL）并抑制了肿瘤生长。在病例 2 中，3D 培养测定中 TMZ 使细胞活力降低 50%，PRL 水平降低 40%。临床上，CAPTEM 非常有效，PRL 水平显著降低（17500→210ng/mL），MRI 显示几乎没有残留肿瘤。
这是首例描述 CAPTEM 治疗难治性泌乳素瘤的报告。体外 3D 球体培养测定可靠地预测了 TMZ 的敏感性，并为选择 TMZ 或 CAPTEM 治疗难治性泌乳素瘤提供了信息。
