Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523.
Department of b Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198.
Radiat Res. 2021 Feb 1;195(2):128-139. doi: 10.1667/RADE-20-00109.1.
Novel synthetic compounds, known as manganese porphyrins (MnPs), have been designed to shift the redox status of both normal cells and cancer cells. When MnPs are coupled with cancer therapies, such as radiation, they have been shown to sensitize tumor cells to treatment and protect normal tissues from damage through the modulation of the redox status of various tissue types. Until now, our preclinical studies have focused on local effects of MnPs and radiation; however, we recognize that successful outcomes for cancer patients involve control of tumor cells throughout the body. In this study, using murine orthotopic mammary tumor models, we investigated how MnPs and radiation influence the development of distant metastasis. We hypothesized that the combination of MnP (MnP/RT), such as MnTnBuOE-2-PyP5+ and radiation treatment (RT) would increase local tumor control via a shift in the intratumoral redox environment, leading to subsequent downregulation of HIF-1 in the primary tumor. Secondarily, we hypothesized that these primary tumor treatment effects would result in a reduction in pulmonary metastatic burden. Balb/c mice with orthotopic 4T1 mammary carcinomas were treated with saline, MnP, RT or MnP/RT. We found MnP/RT did extend local tumor growth delay and overall survival compared to controls and was associated with increased intratumoral oxidative stress. However, the primary tumor growth delay observed with MnP/RT was not associated with a reduced pulmonary metastatic burden. Future directions to investigate the effects of MnP/RT on the development of distant metastasis may include modifications to the radiation dose, the experimental timeline or using a murine mammary carcinoma cell line with a less aggressive metastatic behavior. Clinical trials are underway to investigate the clinical utility of MnTnBuOE-2-PyP5+ for patients undergoing radiotherapy for various tumor types. The promising preclinical data from this study, as well as others, provides support that MnP/RT has the potential to improve local tumor control for these patients.
新型合成化合物，称为锰卟啉（MnPs），旨在改变正常细胞和癌细胞的氧化还原状态。当 MnPs 与放射治疗等癌症治疗方法结合使用时，已证明它们可以通过调节各种组织类型的氧化还原状态使肿瘤细胞对治疗敏感，并保护正常组织免受损伤。到目前为止，我们的临床前研究集中在 MnPs 和放射治疗的局部作用上；然而，我们认识到癌症患者的成功结果涉及对全身肿瘤细胞的控制。在这项研究中，我们使用小鼠原位乳腺肿瘤模型研究了 MnPs 和放射治疗如何影响远处转移的发展。我们假设 MnP（MnP/RT）与辐射治疗（RT）的结合，例如 MnTnBuOE-2-PyP5+ 和放射治疗（RT）会通过改变肿瘤内氧化还原环境来增加局部肿瘤控制，从而导致原发肿瘤中 HIF-1 的下调。其次，我们假设这些原发肿瘤治疗效果将导致肺转移负担减少。用盐水、MnP、RT 或 MnP/RT 治疗具有原位 4T1 乳腺肿瘤的 Balb/c 小鼠。我们发现，与对照相比，MnP/RT 确实延长了局部肿瘤生长延迟和总生存期，并且与肿瘤内氧化应激增加有关。然而，MnP/RT 观察到的原发肿瘤生长延迟与肺转移负担减少无关。进一步研究 MnP/RT 对远处转移发展的影响的方向可能包括改变辐射剂量、实验时间线或使用具有侵袭性较低转移行为的小鼠乳腺癌细胞系。正在进行临床试验以研究 MnTnBuOE-2-PyP5+ 对接受各种肿瘤类型放射治疗的患者的临床应用。这项研究以及其他研究的有希望的临床前数据为 MnP/RT 有可能改善这些患者的局部肿瘤控制提供了支持。
