Department of Women's and Children's Health, Uppsala University, S‑751 85 Uppsala, Sweden.
Department of Medical Sciences, Uppsala University, S‑751 85 Uppsala, Sweden.
Int J Oncol. 2022 Oct;61(4). doi: 10.3892/ijo.2022.5418. Epub 2022 Sep 9.
Epithelial ovarian cancer (EOC) is divided into type I and type II based on histopathological features. Type I is clinically more indolent, but also less sensitive to chemotherapy, compared with type II. The basis for this difference is not fully clarified. The present study investigated the pattern of drug activity in type I and type II EOC for standard cytotoxic drugs and recently introduced tyrosine kinase inhibitors (TKIs), and assessed the association with treatment history and clinical outcome. Isolated EOC tumor cells obtained at surgery were investigated for their sensitivity to seven standard cytotoxic drugs and nine TKIs using a short‑term fluorescent microculture cytotoxicity assay (FMCA). Drug activity was compared with respect to EOC subtype, preoperative chemotherapy, cross‑resistance and association with progression‑free survival (PFS). Out of 128 EOC samples, 120 samples, including 21 type I and 99 type II, were successfully analyzed using FMCA. Patients with EOC type I had a significantly longer PFS time than patients with EOC type II (P=0.01). In line with clinical experience, EOC type I samples were generally more resistant than type II samples to both standard cytotoxic drugs and the TKIs, reaching statistical significance for cisplatin (P=0.03) and dasatinib (P=0.002). A similar pattern was noted in samples from patients treated with chemotherapy prior to surgery compared with treatment‑naive samples, reaching statistical significance for fluorouracil, irinotecan, dasatinib and nintedanib (all P<0.05). PFS time gradually shortened with increasing degree of drug resistance. Cross‑resistance between drugs was in most cases statistically significant yet moderate in degree (r<0.5). The clinically observed relative drug resistance of EOC type I, as well as in patients previously treated, is at least partly due to mechanisms in the tumor cells. These mechanisms seemingly also encompass kinase inhibitors. Ex vivo assessment of drug activity is suggested to have a role in the optimization of drug therapy in EOC.
上皮性卵巢癌 (EOC) 根据组织病理学特征分为 I 型和 II 型。与 II 型相比，I 型在临床上更为惰性，但对化疗的敏感性也较低。造成这种差异的基础尚未完全阐明。本研究调查了 I 型和 II 型 EOC 对标准细胞毒性药物和最近引入的酪氨酸激酶抑制剂 (TKI) 的药物活性模式，并评估了与治疗史和临床结局的关联。在手术中获得的分离的 EOC 肿瘤细胞使用短期荧光微培养细胞毒性测定法 (FMCA) 检测对七种标准细胞毒性药物和九种 TKI 的敏感性。根据 EOC 亚型、术前化疗、交叉耐药性和与无进展生存期 (PFS) 的相关性比较药物活性。在 128 个 EOC 样本中，120 个样本，包括 21 个 I 型和 99 个 II 型，成功地使用 FMCA 进行了分析。EOC 型 I 患者的 PFS 时间明显长于 EOC 型 II 患者 (P=0.01)。与临床经验一致，EOC 型 I 样本通常对标准细胞毒性药物和 TKI 的耐药性均高于 EOC 型 II 样本，顺铂 (P=0.03) 和达沙替尼 (P=0.002) 达到统计学意义。在术前接受化疗的患者的样本中观察到了类似的模式，与未接受治疗的样本相比，氟尿嘧啶、伊立替康、达沙替尼和尼达尼布 (均 P<0.05) 达到统计学意义。随着药物耐药性的增加，PFS 时间逐渐缩短。药物之间的交叉耐药性在大多数情况下具有统计学意义，但程度适中 (r<0.5)。临床上观察到的 EOC 型 I 以及先前治疗患者的相对药物耐药性至少部分归因于肿瘤细胞中的机制。这些机制似乎也包括激酶抑制剂。体外药物活性评估可能在 EOC 药物治疗的优化中发挥作用。
