Showing papers by "Rakesh K. Jain published in 1990"

Interstitial Pressure Gradients in Tissue-isolated and Subcutaneous Tumors: Implications for Therapy

Abstract: High interstitial fluid pressure (IFP) in solid tumors is associated with reduced blood flow as well as inadequate delivery of therapeutic agents such as monoclonal antibodies. In the present study, IFP was measured as a function of radial position within two rat tissue-isolated tumors (mammary adenocarcinoma R3230AC, 0.4-1.9 g, n = 9, and Walker 256 carcinoma, 0.5-5.0 g, n = 6) and a s.c. tumor (mammary adenocarcinoma R3230AC, 0.6-20.0 g, n = 7). Micropipettes (tip diameters 2 to 4 microns) connected to a servo-null pressure-monitoring system were introduced to depths of 2.5 to 3.5 mm from the tumor surface and IFP was measured while the micropipettes were retrieved to the surface. The majority (86%) of the pressure profiles demonstrated a large gradient in the periphery leading to a plateau of almost uniform pressure in the deeper layers of the tumors. Within isolated tumors, pressures reached plateau values at a distance of 0.2 to 1.1 mm from the surface. In s.c. tumors the sharp increase began in skin and levelled off at the skin-tumor interface. These results demonstrate for the first time that the IFP is elevated throughout the tumor and drops precipitously to normal values in the tumor's periphery or in the immediately surrounding tissue. These results confirm the predictions of our recently published mathematical model of interstitial fluid transport in tumors (Jain and Baxter, Cancer Res., 48: 7022-7032, 1988), offer novel insight into the etiology of interstitial hypertension, and suggest possible strategies for improved delivery of therapeutic agents.

Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors.

Abstract: The efficacy in cancer treatment of monoclonal antibodies or other macromolecules bound to radionuclides, chemotherapeutic agents, toxins, enzymes, growth factors, or effector antibodies has been limited by their inability to reach their target in vivo in adequate quantities. Heterogeneity of tumor-associated antigen expression alone has failed to explain the nonuniform uptake of antibodies. As a result, only in recent years have the peculiarities of tumor physiology been recognized as determinants of antibody distribution. Three physiological barriers responsible for the poor localization of macromolecules in tumors have been identified: (a) heterogeneous blood supply; (b) elevated interstitial pressure; and (c) large transport distances in the interstitium. The first barrier limits the delivery of blood-borne molecules to well-perfused regions of a tumor; the second barrier reduces extravasation of fluid and macromolecules in the high interstitial pressure regions and also leads to an experimentally verifiable, radially outward convection in the tumor periphery which opposes the inward diffusion; and the third barrier increases the time required for slowly moving macromolecules to reach distal regions of a tumor. Binding of antibody to an antigen further lowers the effective diffusion rate of the antibody by reducing the amount of mobile antibody. Due to micro- and macroscopic heterogeneities in tumors, the relative magnitude of each of these barriers would vary from one location to another and from one day to the next in the same tumor and from one tumor to another. If the genetically engineered macromolecules, e.g., lymphokines, and other new modalities, e.g., killer lymphocytes, as well as low molecular weight cytotoxic agents, are to fulfill their clinical promise, methods must be developed to overcome these physiological barriers. Some of these methods are discussed, and situations wherein these barriers may not be a problem are pointed out.

Vascular and interstitial barriers to delivery of therapeutic agents in tumors.

Abstract: The efficacy in cancer treatment of novel therapeutic agents such as monoclonal antibodies, cytokines and effector cells has been limited by their inability to reach their target in vivo in adequate quantities. Molecular and cellular biology of neoplastic cells alone has failed to explain the nonuniform uptake of these agents. This is not surprising since a solid tumor in vivo is not just a collection of cancer cells. In fact, it consists of two extracellular compartments: vascular and interstitial. Since no blood-borne molecule or cell can reach cancer cells without passing through these compartments, the vascular and interstitial physiology of tumors has received considerable attention in recent years. Three physiological factors responsible for the poor localization of macromolecules in tumors have been identified: (i) heterogeneous blood supply, (ii) elevated interstitial pressure, and (iii) large transport distances in the interstitium. The first factor limits the delivery of blood-borne agents to well-perfused regions of a tumor; the second factor reduces extravasation of fluid and macromolecules in the high interstitial pressure regions and also leads to an experimentally verifiable, radially outward convection in the tumor periphery which opposes the inward diffusion; and the third factor increases the time required for slowly moving macromolecules to reach distal regions of a tumor. Binding of the molecule to an antigen further lowers the effective diffusion rate by reducing the amount of mobile molecule. Although the effector cells are capable of active migration, peculiarities of the tumor vasculature and interstitium may be also responsible for poor delivery of lymphokine activated killer cells and tumor infiltrating lymphocytes in solid tumors. Due to micro- and macroscopic heterogeneities in tumors, the relative magnitude of each of these physiological barriers would vary from one location to another and from one day to the next in the same tumor, and from one tumor to another. If the genetically engineered macromolecules and effector cells, as well as low molecular weight cytotoxic agents, are to fulfill their clinical promise, strategies must be developed to overcome or exploit these barriers. Some of these strategies are discussed, and situations wherein these barriers may not be a problem are outlined. Finally, some therapies where the tumor vasculature or the interstitium may be a target are pointed out.

Interstitial Transport of Rabbit and Sheep Antibodies in Normal and Neoplastic Tissues

Abstract: Interstitial transport of fluorescein isothiocyanate-conjugated nonspecific polyclonal rabbit and sheep IgG was studied in normal (mature granulation) and neoplastic (VX2 carcinoma) tissues grown in a rabbit ear chamber. The interstitial concentration gradients after i.v. injection were analyzed to yield effective interstitial diffusion coefficients, Deff. The one-dimensional diffusion model underestimated Deff by a factor of up to 3 when compared with a two-dimensional model. Despite marked heterogeneities in Deff, the average values of Deff were higher in tumors than in normal tissue. Rabbit IgG moved faster in tumors than the sheep IgG by a factor of 2. When compared with the dextran of same molecular weight, the ratio of Deff between neoplastic and normal tissue decreased from 33 (dextran) to between 2 and 5 (sheep IgG and rabbit IgG, respectively). When compared with dextran of the same Stokes-Einstein radius, IgGs had a lower Deff in both tissue types. These results are consistent with the size, charge, and configuration of antibodies and the structure and charge of the interstitial matrix and suggest that the delivery of antibodies to tumors may be improved by modulating their charge, hydrophilicity, and antigenicity. The molecular weight dependence of Deff also provides a rational basis for the use of bifunctional antibodies and antibody-enzyme conjugates to increase the delivery of low molecular weight anticancer agents to solid tumors.

Copper-resistant microorganisms and their role in the environment.

Abstract: Naturally occurring, copper-resistant microorganisms are common in the environment. This review discusses the mechanism of copper resistance, which is not yet clearly understood, though the copper resistance conferred by a plasmid pPT23D has been elucidated at the molecular level. The different applications of copper-resistant microorganisms are described, including commerical bloleaching of copper ores. The construction of novel bioleaching strains through recombinant DNA technology may be possible. Biosorbents, the non-living microbial blomass, have been successfully used for metal recovery operations and are also reviewed.

PUVASOL therapy in alopecia areata

Abstract: Thirty two patients having alopecia areata of less than two months duration were inducted into the study. This included 20 males and 12 females. Of the 28 cases who completed the study, 20 (71.42%) showed complete hair regrowth in 14 weeks, out of which 16 (57.14%) had it in 10 weeks and 4 (14.28%) in 14 weeks, 8 methoxy - psoralen (0.75% solution) was applied half an hour prior to the exposure to sunlight, for 30 seconds which was gradually increased to 2 minutes. The procedure was repeated daily. No side effects were observed during the trial.

Anti-stress activity in a muramyl-dipeptide.

Abstract: N-Acetylmuramyl-L-alanyl-D-isoglutamine and some of its derivatives have been examined for anti-stress activity. Amongst these, N-palmitoylmuramyl-L-alanyl-D-isoglutamine is shown to considerably enhance the capacity of animals to endure various types of stress. This indicates that besides acting as immunomodulators and sleep regulators, muramyl dipeptides may also act as anti-stress agents.