The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasion.
The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasion.
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DOI：
10.1158/0008-5472.can-08-2394
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发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
Gatenby RA
中科院分区：
文献类型：
--
作者：
Silva AS;Yunes JA;Gillies RJ;Gatenby RA
许多研究已经表明，癌症中的细胞外pH（pHe）通常低于正常组织中的细胞外pH，并且酸性pHe促进原发性和转移性癌症中的侵袭性肿瘤生长。在这里，我们调查的假设，增加全身浓度的pH缓冲液减少瘤内和瘤周酸中毒，因此，抑制恶性肿瘤的生长。计算机模拟用于量化系统pH缓冲液增加体内肿瘤的酸性pH的能力，并研究用于该目的的最佳缓冲液的化学规格。我们表明，增加血清中碳酸氢钠（NaHCO3）的浓度可以通过已发表的临床试验中使用的摄入量来实现。此外，我们发现，随之而来的肿瘤酸浓度的降低显着减少肿瘤的生长和侵袭，而不改变血液或正常组织的pH值。模拟结果还表明，控制缓冲效果的关键参数是其pKa。这表明pKa为6.1的NaHCO3不是理想的肿瘤内缓冲液，并且使用pKa为约7的缓冲液可以获得更大的肿瘤内pH变化。模拟支持系统pH缓冲液可用于增加肿瘤pH和抑制肿瘤侵袭的假设。
A number of studies have shown that the extracellular pH (pHe) in cancers is typically lower than that in normal tissue and that an acidic pHe promotes invasive tumor growth in primary and metastatic cancers. Here, we investigate the hypothesis that increased systemic concentrations of pH buffers reduce intratumoral and peritumoral acidosis and, as a result, inhibit malignant growth. Computer simulations are used to quantify the ability of systemic pH buffers to increase the acidic pHe of tumors in vivo and investigate the chemical specifications of an optimal buffer for such purpose. We show that increased serum concentrations of the sodium bicarbonate (NaHCO3) can be achieved by ingesting amounts that have been used in published clinical trials. Furthermore, we find that consequent reduction of tumor acid concentrations significantly reduces tumor growth and invasion without altering the pH of blood or normal tissues. The simulations also show that the critical parameter governing buffer effectiveness is its pKa. This indicates that NaHCO3, with a pKa of 6.1, is not an ideal intratumoral buffer and that greater intratumoral pHe changes could be obtained using a buffer with a pKa of ~7. The simulations support the hypothesis that systemic pH buffers can be used to increase the tumor pHe and inhibit tumor invasion.