Testing Adaptive Therapy Protocols using Gemcitabine and Capecitabine on a Mouse Model of Endocrine-Resistant Breast Cancer.
Testing Adaptive Therapy Protocols using Gemcitabine and Capecitabine on a Mouse Model of Endocrine-Resistant Breast Cancer.
复制标题
在内分泌耐药乳腺癌小鼠模型上使用吉西他滨和卡培他滨测试适应性治疗方案。
DOI：
10.1101/2023.09.18.558136
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Maley,CarloC
中科院分区：
文献类型：
--
作者：
Seyedi,Sareh;Teo,Ruthanne;Foster,Luke;Saha,Daniel;Mina,Lida;Northfelt,Donald;Anderson,KarenS;Shibata,Darryl;Gatenby,Robert;Cisneros,Luis;Troan,Brigid;Anderson,AlexanderRA;Maley,CarloC
高效的癌症治疗通常由于获得性耐药性和毒性而面临限制。适应性治疗是一种受生态学启发的方法，旨在通过利用药物敏感和耐药亚克隆之间的竞争性相互作用来控制治疗抗性并最大限度地减少毒性，将患者生存和生活质量置于最大细胞杀伤之上。在为乳腺癌临床试验做准备时，我们使用大量的MCF 7细胞来快速产生内分泌耐药乳腺癌细胞系。然后，我们通过在小鼠异种移植模型中处理内分泌抗性MCF 7细胞来模拟ER+乳腺癌中的二线疗法，以测试卡培他滨、吉西他滨或这两种药物的组合的适应性疗法。单用卡培他滨的剂量调节适应性治疗相对于MTD延长了生存时间，但无统计学显著性（HR：0.22，95% CI 0.043- 1.1 P = 0.065）。然而，当我们在剂量调节（HR = 0.11，95% CI：0.024 - 0.55，P = 0.007）和间歇适应性治疗中交替使用药物时，与高剂量联合治疗（HR = 0.07，95% CI：0.013 - 0.42; P = 0.003）相比，生存时间显著延长。总体而言，无论是单药治疗（P < 0.01）还是联合用药（P < 0.001），生存时间均随剂量减少而延长。适应性治疗方案导致肿瘤增殖细胞比例较低（P = 0.0026）和凋亡细胞较多（P = 0.045）。结果表明，自适应疗法在控制内分泌抵抗性乳腺癌方面优于高剂量疗法，有利于生长较慢的肿瘤，并在两种药物交替方案中显示出前景。
Highly effective cancer therapies often face limitations due to acquired resistance and toxicity. Adaptive therapy, an ecologically inspired approach, seeks to control therapeutic resistance and minimize toxicity by leveraging competitive interactions between drug-sensitive and drug-resistant subclones, prioritizing patient survival and quality of life over maximum cell kill. In preparation for a clinical trial in breast cancer, we used large populations of MCF7 cells to rapidly generate endocrine-resistance breast cancer cell line. We then mimicked second line therapy in ER+ breast cancers by treating the endocrine-resistant MCF7 cells in a mouse xenograft model to test adaptive therapy with capecitabine, gemcitabine, or the combination of those two drugs. Dose-modulation adaptive therapy with capecitabine alone increased survival time relative to MTD, but not statistically significant (HR: 0.22, 95% CI 0.043– 1.1 P = 0.065). However, when we alternated the drugs in both dose modulation (HR = 0.11, 95% CI: 0.024 – 0.55, P = 0.007) and intermittent adaptive therapies significantly increased survival time compared to high dose combination therapy (HR = 0.07, 95% CI: 0.013 – 0.42; P = 0.003). Overall, survival time increased with reduced dose for both single drugs (P < 0.01) and combined drugs (P < 0.001). Adaptive therapy protocols resulted in tumors with lower proportions of proliferating cells (P = 0.0026) and more apoptotic cells (P = 0.045). The results show that Adaptive therapy outperforms high-dose therapy in controlling endocrine-resistant breast cancer, favoring slower-growing tumors, and showing promise in two-drug alternating regimens.
登录
查看更多内容
影响因子：
3.8
作者：
Ramzan,I;Levy,G
通讯作者：
Levy,G
右啡烷对大鼠的抗惊厥作用：可能参与右美沙芬诱导的癫痫发作保护。
影响因子：
6.1
作者：
F. Tortella;J. Ferkany;M. Pontecorvo
通讯作者：
M. Pontecorvo
影响因子：
5
作者：
CZUCZWAR, SJ;JANUSZ, W;KLEINROK, Z
通讯作者：
KLEINROK, Z
右美沙芬和卡倍戊烷：具有新型抗惊厥特性的中枢作用非阿片类镇咳药
影响因子：
2.9
作者：
F. Tortella;J. Musacchio
通讯作者：
J. Musacchio