PDF(Pubmed)
Abstract：
UNASSIGNED: Ovarian cancer is the leading cause of mortality among gynecological malignancies. Carboplatin and poly (ADP-ribose) polymerase inhibitors (PARPi) are often implemented in the treatment of ovarian cancer. Homologous recombination deficient (HRD) tumors demonstrate increased sensitivity to these treatments; however, many ovarian cancer patients are homologous recombination proficient (HRP). TTFields are non-invasive electric fields that induce an HRD-like phenotype in various cancer types. The current study aimed to investigate the impact of TTFields applied together with carboplatin or PARPi (olaparib or niraparib) in preclinical ovarian cancer models.
UNASSIGNED: A2780 (HRP), OVCAR3 (HRD), and A2780cis (platinum-resistant) human ovarian cancer cells were treated in vitro with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or with various drug concentrations. Treated cells were measured for cell count, colony formation, apoptosis, DNA damage, expression of DNA repair proteins, and cell cycle. In vivo, ID8-fLuc (HRP) ovarian cancer cells were inoculated intraperitoneally to C57BL/6 mice, which were then treated with either sham, TTFields (200 kHz), olaparib (50 mg/kg), or TTFields plus olaparib; over a period of four weeks. Tumor growth was analyzed using bioluminescent imaging at treatment cessation; and survival analysis was performed.
UNASSIGNED: The nature of TTFields-drug interaction was dependent on the drug\'s underlying mechanism of action and on the genetic background of the cells, with synergistic interactions between TTFields and carboplatin or PARPi seen in HRP and resistant cells. Treated cells demonstrated elevated levels of DNA damage, accompanied by G2/M arrest, and induction of an HRD-like phenotype. In the tumor-bearing mice, TTFields and olaparib co-treatment resulted in reduced tumor volume and a survival benefit relative to olaparib monotherapy and to control.
UNASSIGNED: By inducing an HRD-like phenotype, TTFields sensitize HRP and resistant ovarian cancer cells to treatment with carboplatin or PARPi, potentially mitigating a-priori and de novo drug resistance, a major limitation in ovarian cancer treatment.
UNASSIGNED: A2780 (HRP), OVCAR3 (HRD), and A2780cis (platinum-resistant) human ovarian cancer cells were treated in vitro with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or with various drug concentrations. Treated cells were measured for cell count, colony formation, apoptosis, DNA damage, expression of DNA repair proteins, and cell cycle. In vivo, ID8-fLuc (HRP) ovarian cancer cells were inoculated intraperitoneally to C57BL/6 mice, which were then treated with either sham, TTFields (200 kHz), olaparib (50 mg/kg), or TTFields plus olaparib; over a period of four weeks. Tumor growth was analyzed using bioluminescent imaging at treatment cessation; and survival analysis was performed.
UNASSIGNED: The nature of TTFields-drug interaction was dependent on the drug\'s underlying mechanism of action and on the genetic background of the cells, with synergistic interactions between TTFields and carboplatin or PARPi seen in HRP and resistant cells. Treated cells demonstrated elevated levels of DNA damage, accompanied by G2/M arrest, and induction of an HRD-like phenotype. In the tumor-bearing mice, TTFields and olaparib co-treatment resulted in reduced tumor volume and a survival benefit relative to olaparib monotherapy and to control.
UNASSIGNED: By inducing an HRD-like phenotype, TTFields sensitize HRP and resistant ovarian cancer cells to treatment with carboplatin or PARPi, potentially mitigating a-priori and de novo drug resistance, a major limitation in ovarian cancer treatment.
摘要：
卵巢癌是妇科恶性肿瘤中死亡的主要原因。卡铂和聚（ADP-核糖）聚合酶抑制剂（PARPi）通常用于治疗卵巢癌。同源重组缺陷（HRD）肿瘤对这些治疗的敏感性增加；然而，许多卵巢癌患者是同源重组（HRP）。TTField是在各种癌症类型中诱导HRD样表型的非侵入性电场。本研究旨在研究TTField与卡铂或PARPi（奥拉帕尼或尼拉帕尼）一起应用于临床前卵巢癌模型的影响。
■A2780(HRP),OVCAR3(HRD),和A2780cis（铂抗性）人卵巢癌细胞在体外用TTField（1V/cmRMS，200kHz,72小时)，单独或与各种药物浓度。测量处理过的细胞的细胞计数,菌落形成,凋亡，DNA损伤,DNA修复蛋白的表达，和细胞周期。在体内,将ID8-fLuc（HRP）卵巢癌细胞腹膜内接种于C57BL/6小鼠，然后用任何一个假的治疗，TTFelds(200kHz),奥拉帕尼（50mg/kg），或TTFields加olaparib；为期四周。在治疗停止时使用生物发光成像分析肿瘤生长;并进行存活分析。
■TTFields-药物相互作用的性质取决于药物的潜在作用机制和细胞的遗传背景，在HRP和耐药细胞中观察到TTField与卡铂或PARPi之间的协同相互作用。处理过的细胞表现出高水平的DNA损伤，伴随着G2/M逮捕，和HRD样表型的诱导。在荷瘤小鼠中，相对于奥拉帕尼单一疗法和对照,TTField和奥拉帕尼共同治疗导致肿瘤体积减小和存活益处。
■通过诱导HRD样表型，TTFelds使HRP和耐药卵巢癌细胞对卡铂或PARPi治疗敏感，可能减轻先验和从头耐药性，卵巢癌治疗的主要限制。
■A2780(HRP),OVCAR3(HRD),和A2780cis（铂抗性）人卵巢癌细胞在体外用TTField（1V/cmRMS，200kHz,72小时)，单独或与各种药物浓度。测量处理过的细胞的细胞计数,菌落形成,凋亡，DNA损伤,DNA修复蛋白的表达，和细胞周期。在体内,将ID8-fLuc（HRP）卵巢癌细胞腹膜内接种于C57BL/6小鼠，然后用任何一个假的治疗，TTFelds(200kHz),奥拉帕尼（50mg/kg），或TTFields加olaparib；为期四周。在治疗停止时使用生物发光成像分析肿瘤生长;并进行存活分析。
■TTFields-药物相互作用的性质取决于药物的潜在作用机制和细胞的遗传背景，在HRP和耐药细胞中观察到TTField与卡铂或PARPi之间的协同相互作用。处理过的细胞表现出高水平的DNA损伤，伴随着G2/M逮捕，和HRD样表型的诱导。在荷瘤小鼠中，相对于奥拉帕尼单一疗法和对照,TTField和奥拉帕尼共同治疗导致肿瘤体积减小和存活益处。
■通过诱导HRD样表型，TTFelds使HRP和耐药卵巢癌细胞对卡铂或PARPi治疗敏感，可能减轻先验和从头耐药性，卵巢癌治疗的主要限制。
