title: Pharmacologic modification of tumor blood flow and interstitial fluid pressure in a human tumor xenograft: network analysis and mechanistic interpretation.
abstract: 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.
authors.affiliation: Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Zlotecki
authors.forename: L T
authors.initials: LT
authors.lastname: Baxter
authors.forename: Y
authors.initials: Y
authors.lastname: Boucher
authors.forename: R K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D003110:Colonic Neoplasms / Q000098:blood supply*; D004837:Epinephrine / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects*; D005260:Female; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D008962:Models, Theoretical; D009368:Neoplasm Transplantation; D005996:Nitroglycerin / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects*; D014183:Transplantation, Heterologous
chemical_list: D000804:Angiotensin II; D006830:Hydralazine; D005996:Nitroglycerin; D009638:Norepinephrine; D004837:Epinephrine