Interstitial pressure

In arterioles, the hydrostatic pressure is about 37 mm Hg, with an interstitial (tissue) pressure of 1 mm Hg opposing it. The osmotic pressure (oncotic pressure) exerted by the plasma proteins is approximately 25 mm Hg. Thus, a net outward force of about 11 mm Hg drives fluid out into the interstitial spaces. In venules, the hydrostatic pressure is about 17 mm Hg, with the oncotic and interstitial pressures as described above thus, a net force of about 9 mm Hg attracts water back into the circulation. The above pressures are often referred to as the Starling forces. If the concentration of plasma proteins is markedly diminished (eg, due to severe protein malnutrition), fluid is not attracted back into the intravascular compartment and accumulates in the extravascular tissue spaces, a condition known as edema. Edema has many causes protein deficiency is one of them. 

LT Baxter, RK Jain. Transport of fluid and macromolecules in tumors. I. Role of interstitial pressure and convection. Microvasc Res 37 77-104, 1989. 

Diffusion, particularly of macromolecules, plays a minor role in transport across this barrier. Convection due to leaky blood vessels, on the other hand, should enhance delivery yet the movement of drugs and macromolecnles into the interstitinm is often surprisingly limited. This is generally attributed to a diminished hydrostatic pressure gradient between the vascular compartment and the interstitium, which is explained by decreased vascnlar pressure or increased interstitial pressure, or both. 

There are several consequences of these anomalies in pressnre gradients for the delivery and distribution of drugs and macromolecules within the tnmonr interstitinm. First, high interstitial pressures mean that the central regions of the tnmonr, already poorly perfused, demonstrate low or non-existent convective flow into the interstitinm. Fnrthermore, interstitial convective flow will tend to radiate outward from the centre, towards the periphery and regions of lower interstitial pressure. Therefore, only small amonnts of drngs or macromolecules will reach cells in the centre of the tumour. At the tumour periphery, where convective transfer across the blood vessel wall might take place, further movement towards the centre of the tumour will be impeded by bulk flow in the opposite direction. 

As mentioned in Section 8.4.2, elevated interstitial pressure, heterogeneous and reduced functional vasculature, and the relatively large distances that Mabs have to travel in the tumour interstitium, are hurdles which need to be overcome in the pursuit of efficient drug targeting. The relatively large molecular weight of Mabs (approximately 150 kDa) [2,14], also... 

The conflicting results discussed above suggest that further studies are required for understanding mechanisms of convection. More specifically, it is important to investigate hydraulic conductivity, interstitial pressure, and retardation coefficient in different tumor tissues, and how these factors are coupled with infusion-induced tissue deformation. 

The major problem of gene therapy is the low transduction efficiency in vivo. For the application to cancer this problem is exacerbated by the inefficient vascularization and high interstitial pressure in malignant tumors, which limit the accessibility for any kind of vector. One possibility to address this problem is the use of viruses that are able to replicate in vivo and thereby spread throughout the tumor tissue. This approach is not only useful for the improved delivery of therapeutic proteins but seems particularly appealing if combined with the intrin-... 

Anti-tumor activity of bevacizumab has been reported in various preclinical animal models (primary and metastatic) with a broad array of tumor types [106, 107]. Clinical studies have further validated the focal role of VEGF in cancer. A single infusion of bevacizumab at 5 mg/kg in patients with primary and locally advanced adenocarcinoma of the rectum demonstrated direct and rapid antivascular effect in human tumors, with decreases in tumor perfusion, vascular volume, microvascular density, and interstitial pressure [108]. Clinical efficacy of bevacizumab in combination with 5-FU- and irinotecan-based regimens has been demonstrated in patients with metastatic colorectal cancer a significant improvement in overall survival time was observed compared with chemotherapy alone (20.3 versus 15.6 months for chemotherapy plus bevacizumab versus chemotherapy alone) [109]. 

The reverse flux of fluid from the interstitial to the vascular space (14) is caused by increased interstitial fluid pressure (12) and increased plasma protein concentration (oncotic pressure), hyperosmotemia, or both depending upon the intensity (above or below 50 -peak capacity) and duration of the exercise. Increased interstitial hydrostatic pressure and increased plasma osmotic pressures retard the fluid shift from plasma to the interstitium. Equilibrium is reached when interstitial pressure balances capillary filtration pressure (24). After cessation of exercise, restitution of plasma volume takes 40-60 minutes (21,22) unless significant dehydration is present. The immediate post-exercise hyperosmotemia, the relative hyperproteinemia, and the reduction in systemic blood pressure contribute to the restoration of plasma volume. The reduction in blood pressure, which produces a fall in local hydrostatic pressure within the capillaries of the previously active muscle, is probably the single most important factor. 

A high interstitial pressure in the tumor combined with additional edema due to leakage of increased intracellular sodium after permeabihzation, leading to further compression of the already collapsed tumor capillaries. 

Corticosteroids are used in clinical practice to relieve pressure symptoms caused by many tumor types, notably intracerebral tumors but also those causing airway or central venous obstruction. Their mode of action has been studied in animals (57) and humans (58), and is thought to involve first constriction of tumor vascular volume and then a reduction in water content. Reduced interstitial pressure should increase perfusion and extravascular diffusion rates, and high doses of steroids have been shown to increase blood flow in human colonic tumors transplanted into mice. Uptake of antibody into tumors has been assessed before and after administration of high-dose dexamethasone to decrease tumor interstitial pressure and thus increase antigen accessibility. Three patients with recurrent colorectal carcinoma had two antibody scans each, 72 h apart, and the injected dose was the same for all scans (20 mg). Dexamethasone was started 24 h before the second dose of antibody, with an initial iv dose of 10 mg followed by 4 mg four times daily orally for 48 h. 

Relative concentrations of CEA in tumor and normal tissues are such that targeting each molecule would result in very high tumor normal tissue ratios adequate for radioimmunotherapy. In practice, most of the tumor CEA is unbound because of inhomogeneities in the microenvironment and raised interstitial pressure, as well as inadequate antibody dose (normal tissues unsaturated) and low binding affinity. 

Jain, R. K. and Baxter, L. T. (1988) Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumours significance of raised interstitial pressure. Cancer Res. 48, 7022-7032. 

Curti, B. D., Urba, W. J., Alvord, W. G., et al. (1993) Interstitial pressure of subcutaneous nodules in melanoma and lymphoma patients changes during treatment. Cancer Res. 53, 2204. 

What are the components of the safety factor There are in fact three key components the negative interstitial pressure, the capacity of the lymphatic system to transport more fluid than it does under normal circumstances and the fact that increased lymph drainage tends to wash protein out of the interstitial spaces, thus reducing perimicrovascular osmotic pressure. 

Fig. 2. Physiological barriers that a blood-borne molecule encounters before it reaches a cancer cell in a solid tumor, (a) Schematic of a heterogeneously perfused tumor showing well-vascularized periphery a semi-necrotic, intermediate zone and an avascularized, necrotic central region. Note that immediately after i.v. injection, the molecules are delivered to perfused regions only, (b) Low interstitial pressure in the periphery permits adequate extravasation of fluid and macromolecules.

Jain, 1989). Since transvascular transport by diffusion is slow for a macromolecule to begin with, macromolecular extravasation would be very small in the high interstitial pressure regions of a tumor. Since high-pressure regions usually coincide with regions of poor perfusion rate and lower vessel surface area, leakage of blood-borne macromolecules from vessels would be further restricted (Baxter and Jain, 1990). 

Fig. 6. (a) Interstitial pressure gradients in the mammary adenocarcinoma R3230AC as a function of radial position. The circles ( ) represent data points (Boucher et al., 1990), and the solid line represents the theoretical profile based on our previously developed mathematical model (Jain and Baxter, 1988 Baxter and Jain, 1989). Note that the pressure is nearly uniform in most of the tumor, but drops precipitously to normal tissue values in the periphery. Elevated pressure in the central region retards the extravasation of fluid and macromolecules. In addition, the pressure drop from the center to the periphery leads to an experimentally verifiable, radially outward fluid flow. (Reproduced from Boucher et al., 1990, with permission.) (b) Microvascular pressure (MVP) in the peripheral vessels of the mammary adenocarcinoma R3230AC is comparable to the central interstitial fluid pressure (IFP) (adapted from Boucher and Jain, 1992). These results suggest that osmotic pressure difference across vessel walls is small in this tumor. 

Interstitial fluid pressures in normal tissues are approximately atmospheric or slightly sub-atmospheric, but pressures in tumors can exceed atmospheric by 10 to 30mmHg, increasing as the tumor grows. For 1-cm radius tumors, elevated interstitial pressures create an outward fluid flow of 0.1 fim/s [11]. Tumors experience high interstitial pressures because (i) they lack functional lymphatics, so that normal mechanisms for removal of interstitial fluid are not available, (ii) tumor vessels have increased permeability, and (iii) tumor cell proliferation within a confined volume leads to vascular collapse [12]. In both tissue-isolated and subcutaneous tumors, the interstitial pressure is nearly uniform in the center of the tumor and drops sharply at the tumor periphery [13]. Experimental data agree with mathematical models of pressure distribution within tumors, and indicate that two parameters are important determinants for interstitial pressure the effective vascular pressure, (defined in Section 6.2.1), and the hydraulic conductivity ratio, (also defined in Section 6.2.1) [14]. The pressure at the center of the tumor also increases with increasing tumor mass. 

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