Predicting the safety and efficacy of buffer therapy to raise tumour pHe: an integrative modelling study.
Predicting the safety and efficacy of buffer therapy to raise tumour pHe: an integrative modelling study.
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DOI：
10.1038/bjc.2012.58
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发表时间：
2012-03-27
影响因子：
8.8
通讯作者：
Maini, P. K.
中科院分区：
文献类型：
--
作者：
Martin, N. K.;Robey, I. F.;Gaffney, E. A.;Gillies, R. J.;Gatenby, R. A.;Maini, P. K.
临床正电子发射断层成像显示，与邻近正常组织相比，绝大多数人类癌症表现出显著增加的葡萄糖代谢，导致酸性肿瘤微环境。最近的研究表明，通过系统缓冲降低这种酸度可以显著抑制小鼠异种移植物转移瘤的发育和生长。我们应用并扩展了先前开发的血液和肿瘤缓冲数学模型，以检查口服碳酸氢盐缓冲剂对小鼠的影响，以及对人类的潜在影响。我们总结了实验观察到的缓冲疗法对肿瘤pHe的影响，并在小鼠体内测试了模型预测。我们将模型参数化到人类，以确定转化安全性和有效性，并预测可能增强治疗反应的患者亚组，以及最有希望的联合或替代缓冲疗法。该模型预测了先前未见的由碳酸氢盐治疗引起的小鼠血液pHe升高的潜在危险，我们的体内实验证实了这一点。模拟结果显示，碳酸氢盐的疗效有限，尤其是对患有侵袭性癌症的人。我们预测缓冲疗法将是最有效的：在老年患者或个体肾损害；与质子产生抑制剂（如二氯乙酸）、肾小球滤过率抑制剂（如非甾体抗炎药和血管紧张素转换酶抑制剂）联合使用，或与具有7.1-7.2最佳pK的替代缓冲试剂联合使用。我们的数学模型证实，碳酸氢盐是提高肿瘤pHe的有效药物，但在肿瘤pHe正常化所需的高剂量下，可能会诱发代谢性碱中毒。我们预测，在pK值7.1-7.2的老年患者中使用或与质子产生抑制剂或缓冲液联合使用是最有希望的。
Clinical positron emission tomography imaging has demonstrated the vast majority of human cancers exhibit significantly increased glucose metabolism when compared with adjacent normal tissue, resulting in an acidic tumour microenvironment. Recent studies demonstrated reducing this acidity through systemic buffers significantly inhibits development and growth of metastases in mouse xenografts. We apply and extend a previously developed mathematical model of blood and tumour buffering to examine the impact of oral administration of bicarbonate buffer in mice, and the potential impact in humans. We recapitulate the experimentally observed tumour pHe effect of buffer therapy, testing a model prediction in vivo in mice. We parameterise the model to humans to determine the translational safety and efficacy, and predict patient subgroups who could have enhanced treatment response, and the most promising combination or alternative buffer therapies. The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our in vivo experiments. Simulations predict limited efficacy of bicarbonate, especially in humans with more aggressive cancers. We predict buffer therapy would be most effectual: in elderly patients or individuals with renal impairments; in combination with proton production inhibitors (such as dichloroacetate), renal glomular filtration rate inhibitors (such as non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1–7.2. Our mathematical model confirms bicarbonate acts as an effective agent to raise tumour pHe, but potentially induces metabolic alkalosis at the high doses necessary for tumour pHe normalisation. We predict use in elderly patients or in combination with proton production inhibitors or buffers with a pK of 7.1–7.2 is most promising.
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