Extravascular transport in normal and tumor tissues

https://doi.org/10.1016/S1040-8428(86)80023-3Get rights and content

The transport characteristics of the normal and tumor tissue extravascular space provide the basis for the determination of the optimal dosage and schedule regimes of various pharmacological agents in detection and treatment of cancer. In order for the drug to reach the cellular space where most therapeutic action takes place, several transport steps must first occur: (1) tissue perfusion; (2) permeation across the capillary wall; (3) transport through interstitial space; and (4) transport across the cell membrane. Any of these steps including intracellular events such as metabolism can be the rate-limiting step to uptake of the drug, and these rate-limiting steps may be different in normal and tumor tissues. This review examines these transport limitations, first from an experimental point of view and then from a modeling point of view. Various types of experimental tumor models which have been used in animals to represent human tumors are discussed. Then, mathematical models of extravascular transport are discussed from the prespective of two approaches: compartmental and distributed. Compartmental models lump one or more sections of a tissue or body into a “compartment” to describe the time course of disposition of a substance. These models contain “effective” parameters which represent the entire compartment. Distributed models consider the structural and morphological aspects of the tissue to determine the transport properties of that tissue. These distributed models describe both the temporal and spatial distribution of a substance in tissues. Each of these modeling techniques is described in detail with applications for cancer detection and treatment in mind.

References (369)

  • ReinholdH.S.

    Improved microcirculation in irradiated tumors

    Eur. J. Cancer

    (1971)
  • DimitrievichG.S. et al.

    In vivo measurement of microvasculature: a method for repeated and reproducible quantiating long-term experiments

    Microvasc. Res.

    (1979)
  • CarterS.K. et al.
  • BertinoJ.R.

    Folate antagonists as chemotherapeutic agents

    Ann. N. Y. Acad. Sci.

    (1971)
  • BleyerW.A.

    The clinical pharmacology of methotrexate: new applications of an old drug

    Cancer

    (1978)
  • SteelG.G.
  • SwannG.W.

    Some Current Mathematical Topics in Cancer Research, University Microfilms, Int., Ann Arbor, Mich

    (1977)
  • GerweckL.E. et al.

    Response of cells to hyperthermia under acute and chronic hypoxic conditions

    Cancer Res.

    (1979)
  • GoldsteinA. et al.
  • HutchinsonD.J. et al.

    Effects of selected anticancer drugs on the survival time of mice with L1210 leukemia: relative responses of antimetabolite-resistant strains

    Cancer Res.

    (1962)
  • KesselD. et al.

    Amethopterin transport in Ehrlich ascites carcinoma and L1210 cells

    Cancer Res.

    (1967)
  • SirotnakF.M. et al.

    Differential permeability and the basis for selective activity of methotrexate during therapy of the L1210 leukemia

    Cancer Res.

    (1973)
  • ChelloP.L. et al.

    Alterations in the kinetics of methotrexate transport during growth of L1210 murine leukemia cells in culture

    Mol. Pharmacol.

    (1980)
  • ChanK.K. et al.

    A fluorometric determination of adriamycin and its metabolites in biological tissue

    Res. Commun. Chem. Pathol. Pharmacol.

    (1973)
  • LoefflerL.J. et al.

    A radioimmunoassay for methotrexate and its comparison with spectrofluorimetric procedures

    Cancer Res.

    (1976)
  • SizotnakF.M. et al.

    Comparative studies on the transport of aminopterin, methotrexate, and methasquin by the L1210 leukemia cell

    Cancer Res.

    (1972)
  • WerkheiserW.C. et al.

    Assay for 4-amino folic acid analogues by inhibition of folic acid reductase

    J. Pharmacol. Exp. Ther.

    (1962)
  • MengatoR.

    Effects of Hyperthermia on the Development of Necrosis in Multicell Spheroids

  • SutherlandR.M. et al.

    Growth of multicell spheroids in tissue culture as a model of nodular carcinomas

    J. Natl. Cancer Inst.

    (1973)
  • NedermanT. et al.

    Penetration of therapeutically interesting substances into cellular spheroids

  • MuirheadK.A. et al.

    Flow cytometric determination of adriamycin distribution within EMT6/Ro spheroids, paper presented at the Int

  • WestG. et al.

    Methotrexate (MTX) penetration of human osteosarcoma spheroids: a proposed model for solid tumor resistance to adjuvant chemotherapy

  • ErlichmanC. et al.

    Cytotoxicity of adriamycin in MGU-U1 cells grown as monolayer cultures, spheroids, and xenografts in immune-deprived mice

    Cancer Res.

    (1984)
  • LiebletA.G. et al.

    Transplantation of Tumors

    (1967)
  • WeissL.

    Contact between cancer cells and other cells: a biophysical approach

  • GullinoP.M. et al.

    Studies on the exchange of fluids between host and tumor. I. A. method for growing

    J. Natl. Cancer Inst.

    (1961)
  • GullinoP.M.

    Techniques for the study of tumor pathophysiology

  • GranthamR. et al.

    Primary mammary tumors connected to the host by a single artery and vein

    J. Natl. Cancer Inst.

    (1973)
  • JainR.K. et al.

    Pharmacokinetics of methotrexate in solid tumors

    J. Pharmacokinet. Biopharmacol.

    (1979)
  • FolkmanJ. et al.

    Growth and metastasis of tumor in organ culture

    Cancer

    (1963)
  • FolkmanJ. et al.

    Tumor behavior in isolated perfused organs: in vitro growth and metastases of biopsy material in rabbit thyroid and canine intestinal segment

    Ann. Surg.

    (1966)
  • GullinoP.M.

    In vitro perfusion of tumors

  • GullinoP.M. et al.

    The interstitial fluid of solid tumors

    Cancer Res.

    (1964)
  • GullinoP.M.

    Extracellular compartments of solid tumors

  • GullinoP.M.

    In vivo utilization of oxygen and glucose by neoplastic tissue

  • WattersC. et al.

    Translocation of DNA from the vascular into the nuclear compartment of solid mammary tumors

    Cancer Res.

    (1971)
  • JainR.K. et al.

    Continuous non-invasive monitoring of pH and temperature of rat Walker 256 carcinosarcoma: during normo-and hyperglycemia

    J. Natl. Cancer. Inst.

    (1984)
  • WiedemanM.P. et al.
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