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L T Baxter

Publications and source records attributed to L T Baxter.

23 records · Page 2Linked to original sources
PubMed1990

Transport of fluid and macromolecules in tumors. II. Role of heterogeneous perfusion and lymphatics.

We have recently developed a general theoretical framework for transvascular exchange and extravascular transport of fluid and macromolecules in tumors. The model was applied to a homogeneous, alymphatic tumor with no extravascular binding. For this simplified system, the interstitial pressure was found to be a major contributing factor to the heterogeneous distribution of macromolecules within solid tumors. A steep pressure gradient was predicted at the periphery of the tumor. Our recent experiments have verified these predicted profiles. The purpose of this investigation was to apply this theoretical framework to the more realistic case of a nonuniformly perfused tumor. The role of lymphatics for macromolecular transport was also studied using the model. The uptake and distribution of IgG and its fragment, Fab, were simulated. The novel result from this work is that necrosis does not reduce the central interstitial pressure in a tumor. Other results showed that (i) macromolecules do not penetrate a necrotic core at early times after injection; (ii) at longer time periods after a bolus injection (days for Fab, months for IgG in a tumor of radius approximately 1cm) a "reservoir" of material may be formed in the necrotic core; (iii) continuous infusion or repeated injections should maintain a higher interstitial concentration of macromolecules; and (iv) lymphatics, if present in a tumor, would rapidly remove material and result in much lower concentration levels. The model is also used to explain some previous experimental data in the literature on antibody distribution.

Animals↗
PubMed1989

Transport of fluid and macromolecules in tumors. I. Role of interstitial pressure and convection.

A general theoretical framework for transvascular exchange and extravascular transport of fluid and macromolecules in tumors is developed. The resulting equations are applied to the most simple case of a homogeneous, alymphatic tumor, with no extravascular binding. Numerical simulations show that in a uniformly perfused tumor the elevated interstitial pressure is a major cause for heterogeneous distribution of nonbinding macromolecules, because it (i) reduces the driving force for extravasation of fluid and macromolecules in tumors, (ii) results in nonuniform filtration of fluid and macromolecules from blood vessels, and (iii) leads to experimentally verifiable, radially outward convection which opposes the inward diffusion. The models are used to predict the interstitial pressure, interstitial fluid velocity, and concentration profiles as a function of radial position and tumor size. The model predictions agree with the following experimental data: (i) the interstitial pressure in a tumor is lowest at the periphery of the tumor and increases towards the center; (ii) the radially outward fluid velocity predicted by the fluid transport model is of the same order of magnitude as that measured in tissue-isolated tumors; and (iii) the concentration of macromolecules is higher in the periphery than in the center of tumors at short times postinjection; however, at later times the peripheral concentration is less than the concentration in the center. This work shows that in addition to the heterogeneous distribution of blood supply, hindered interstitial transport, and rapid extravascular binding of macromolecules (e.g., monoclonal antibodies), the elevated interstitial pressure plays an important role in determining the penetration of macromolecules into tumors. If the genetically engineered macromolecules are to fulfill their clinical promise, methods must be developed to overcome these physiological barriers in tumors.

Animals↗
PubMed1988

Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure.

The therapeutic efficacy of monoclonal antibodies (MAbs), bound to radionuclides, chemotherapeutic agents, toxins, growth factors, or effector antibodies, depends upon their ability to reach their target in vivo in adequate quantities. Despite the high vascular permeability and interstitial transport coefficients in tumor tissue compared to several normal tissues, MAbs and their fragments do not distribute homogeneously in a tumor. Heterogeneity of tumor-associated antigen expression alone cannot explain this maldistribution of MAbs in tumors. We propose that in addition to the heterogeneous blood perfusion, hindered diffusion in the interstitium, and extravascular binding of MAbs, elevated interstitial pressure is responsible for the poor penetration of MAbs into tumors. Elevated interstitial pressure principally reduces the driving force for extravasation of fluid and macromolecules in tumors, and also leads to an experimentally verifiable, radially outward convection which opposes the inward diffusion. We present here mathematical models for transport of fluid and macromolecules in a tumor. To illustrate the significance of elevated interstitial pressure, these models are used to describe the interstitial pressure, interstitial fluid velocity, and concentration of nonbinding macromolecules as a function of radial position in a uniformly perfused tumor. The key result of these models is that the filtration of fluid from blood vessels in a uniformly perfused tumor is (a) spatially heterogeneous, (b) a result of elevated interstitial pressure, and (c) sufficient to explain the heterogeneous distribution of macromolecules in tumors. Nonuniform blood flow, and extravascular binding would enhance this heterogeneity in the solute distribution considerably. The results of the models also agree with the following experimental data: (a) tumor interstitial pressure is low in the periphery and it increases toward the center of the tumor; (b) the radially outward fluid velocity at the tumor periphery predicted by the model is of the same order of magnitude as measured in tissue-isolated tumors; and (c) immediately after bolus injection, the concentration of macromolecules is higher in the periphery than in the center; however, at later time periods the peripheral concentration is lower than in the center. These results have significant implications not only for MAbs and their fragments, but for other biologically useful macromolecules (e.g., cytokines) produced by genetic engineering for cancer diagnosis and treatment.

Antibodies, Monoclonal↗
PubMed1987

Vascular permeability and interstitial diffusion of macromolecules in the hamster cheek pouch: effects of vasoactive drugs.

A simple one-dimensional mathematical model which relates the number of "leaky" sites in postcapillary venules to the extravasation of macromolecules in terms of an effective microvascular permeability, P, and an effective interstitial diffusion coefficient, D, is developed. The model is used to analyze the data of E. Svensjö and K. Roempke [in "Progress in Microvascular Research II" (F. C. Courtice, D. C. Garlick, and M. A. Perry, Eds.), pp. 449-463, 1984] and C. G. A. Persson and E. Svensjö [in "Handbook of Inflammation" (J. L. Bonta, M. A. Bray, and M. J. Parnham, Eds.), pp. 61-82, 1985] for the transport of 70,000 molecular weight dextran in a hamster cheek pouch prior to and following topical application of two vasoactive agents: histamine and bradykinin. D ranged from 2.2 to 4.0 X 10(-9) cm2/sec, and P was found to be 4.1 X 10(-8) cm/sec. The increased number of leaky sites resulted in a sixfold increase in P due to histamine, at a dose of 2.5 X 10(-6) M, and a fourfold increase in P due to bradykinin, at a dose of 4.0 X 10(-7) M.

Animals↗