Zlotecki R A, Baxter L T, Boucher Y, Jain R K
Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Microvasc Res. 1995 Nov;50(3):429-43. doi: 10.1006/mvre.1995.1069.
Various vasoactive agents have been used to modify tumor blood flow with the ultimate goal of improving cancer detection and treatment, with widely disparate results. Furthermore, the lack of mechanistic interpretations has hindered understanding of how these agents affect the different physiological parameters involved in perfusion. Thus, there is a need to develop a unified framework for understanding the interrelated physiological effects of pharmacological and physical agents. The goals of this study were (1) to develop a mathematical model which helps determine the location and magnitude of changes in the vascular resistance of tumor and normal tissues and (2) to test the model with our experimental studies and by comparison with results from the literature. The systemic and interstitial pressures and relative tumor blood flow were measured before and after administration of angiotensin II, epinephrine, norepinephrine, nitroglycerin, and hydralazine in SCID mice bearing LS174T human colon adenocarcinoma xenografts. A mathematical model was developed in analogy to electrical circuits which examined the pressure, flow, and resistance relationships for arterial and venous segments of the vasculature of a tumor and surrounding normal tissue. Vasoconstrictor-induced increases in the mean arterial blood pressure led to increases in tumor blood flow and interstitial pressure with the magnitude of change dependent on the agent (percentage change in blood flow: angiotensin > epinephrine > norepinephrine). The vasodilating agents induced decreases in tumor blood flow in parallel to the induced decreases in the systemic pressure, but only the long-acting arterial vasodilator hydralazine was capable of effecting a decrease in tumor interstitial pressure. The model was also found to be consistent with other data available in the literature on norepinephrine, pentoxifylline, nicotinamide, and hemodilution, and was useful in providing input as to the location and degree of the physiological effects of these agents. The results of the data and model show that the steal phenomenon is the dominant mechanism for redistribution of host blood flow to the tumor. However, some degree of arterial control was found to be present in the tumors. Moreover, the parallel increases in tumor interstitial pressure and blood flow contradict any hypothesis suggesting that elevated interstitial fluid pressure precipitates chronic vascular collapse, thus decreasing blood flow.
为改善癌症检测与治疗，人们使用了多种血管活性药物来调节肿瘤血流，但结果差异很大。此外，由于缺乏机理解释，阻碍了人们对这些药物如何影响灌注中不同生理参数的理解。因此，需要建立一个统一的框架来理解药理和物理因素的相关生理效应。本研究的目标是：（1）建立一个数学模型，以帮助确定肿瘤组织和正常组织血管阻力变化的位置和大小；（2）通过我们的实验研究并与文献结果进行比较来测试该模型。在携带LS174T人结肠腺癌异种移植瘤的SCID小鼠中，测量了给予血管紧张素II、肾上腺素、去甲肾上腺素、硝酸甘油和肼苯哒嗪前后的全身和间质压力以及相对肿瘤血流。我们开发了一个类似于电路的数学模型，该模型研究了肿瘤及其周围正常组织脉管系统动脉段和静脉段的压力、血流和阻力关系。血管收缩剂引起的平均动脉血压升高导致肿瘤血流和间质压力升高，变化幅度取决于药物（血流百分比变化：血管紧张素>肾上腺素>去甲肾上腺素）。血管扩张剂引起肿瘤血流减少，与全身压力降低平行，但只有长效动脉血管扩张剂肼苯哒嗪能够降低肿瘤间质压力。该模型还与文献中关于去甲肾上腺素、己酮可可碱、烟酰胺和血液稀释的其他数据一致，有助于提供这些药物生理效应的位置和程度方面的信息。数据和模型结果表明，窃血现象是宿主血流重新分布至肿瘤的主要机制。然而，发现肿瘤中存在一定程度的动脉控制。此外，肿瘤间质压力和血流的平行增加与任何认为间质液压力升高会导致慢性血管塌陷从而减少血流的假设相矛盾。
