Khalighfard Solmaz, Alizadeh Ali Mohammad, Poorkhani Amirhoushang, Motahari Mohammadmehdi, Tahmasebifar Arash, Omranipour Ramesh, Keshavarz Pedram, Haddad Peiman
Radiation Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Breast Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran; Cancer Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Eur J Pharmacol. 2020 Dec 15;889:173605. doi: 10.1016/j.ejphar.2020.173605. Epub 2020 Sep 24.
Since only a minority of patients may respond to single-agent therapies, methods to test the potential antitumor activity of rational combination therapies are still needed. This study aimed to characterize the efficacy of antitumor combination therapies in vivo within the primary tumor using patient-derived xenograft (PDX) models by gamma-irradiation-induced immune suppression. We employed four Luminal A PDX models obtained from human mammary tumors grown in mice. PDX models were implanted into the right flank of mice, and treatments have ensued once tumor volume reached ~150 mm. Four of the active drugs- Adriamycin, Cyclophosphamide, Taxotere, and Tamoxifen-were tested in vivo to treat mammary tumors. The tumor volume was measured during the study. The mice's immune system was inherently suppressed by gamma irradiation, thus allowing human tumors to grow. The results showed that the tumorigenesis rate of the PDX model was from 65 to 80%. PDX models were successfully established with a high frequency of tumor engraftment. Humanized mice treated with a two-drug regimen, that is, adriamycin + cyclophosphamide exhibited an increased antitumor response than a three-drug regimen, that is, adriamycin + cyclophosphamide + taxotere that correlated with tumor growth inhibition. Combination therapies with adriamycin + cyclophosphamide in PDX mice reduced tumor growth in four Luminal A PDX models. These preclinical results suggest that a two-drug regimen than a three-drug regimen can be useful for breast cancer patients. This study provides insights for future studies combining chemotherapeutics with targeted therapies using PDX models by gamma-irradiation-induced immune suppression.
由于只有少数患者可能对单药治疗有反应，因此仍需要测试合理联合治疗潜在抗肿瘤活性的方法。本研究旨在通过γ射线诱导的免疫抑制，利用患者来源的异种移植（PDX）模型在原发性肿瘤体内表征抗肿瘤联合治疗的疗效。我们使用了从在小鼠体内生长的人乳腺肿瘤获得的四种Luminal A PDX模型。将PDX模型植入小鼠右侧胁腹，一旦肿瘤体积达到约150立方毫米，便开始进行治疗。在体内测试了四种活性药物——阿霉素、环磷酰胺、多西他赛和他莫昔芬——以治疗乳腺肿瘤。在研究过程中测量肿瘤体积。小鼠的免疫系统通过γ射线照射被内在抑制，从而使人类肿瘤得以生长。结果表明，PDX模型的肿瘤发生率为65%至80%。以高肿瘤植入频率成功建立了PDX模型。用两药方案（即阿霉素+环磷酰胺）治疗的人源化小鼠比三药方案（即阿霉素+环磷酰胺+多西他赛）表现出更高的抗肿瘤反应，这与肿瘤生长抑制相关。在PDX小鼠中，阿霉素+环磷酰胺的联合治疗在四种Luminal A PDX模型中均降低了肿瘤生长。这些临床前结果表明，两药方案比三药方案对乳腺癌患者可能更有用。本研究为未来利用γ射线诱导的免疫抑制，将化疗与靶向治疗相结合的PDX模型研究提供了见解。
