PMID- 3191477
OWN - NLM
STAT- MEDLINE
DCOM- 19890109
LR  - 20220309
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 48
IP  - 24 Pt 1
DP  - 1988 Dec 15
TI  - Mechanisms of heterogeneous distribution of monoclonal antibodies and other 
      macromolecules in tumors: significance of elevated interstitial pressure.
PG  - 7022-32
AB  - 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.
FAU - Jain, R K
AU  - Jain RK
AD  - Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, 
      Pennsylvania 15213-3890.
FAU - Baxter, L T
AU  - Baxter LT
LA  - eng
GR  - CA-36902/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antibodies, Monoclonal)
SB  - IM
MH  - Antibodies, Monoclonal/*pharmacokinetics
MH  - Capillary Permeability
MH  - Extracellular Space/*metabolism
MH  - Mathematics
MH  - *Models, Biological
MH  - Molecular Weight
MH  - Neoplasms/*metabolism
MH  - Pressure
EDAT- 1988/12/15 00:00
MHDA- 1988/12/15 00:01
CRDT- 1988/12/15 00:00
PHST- 1988/12/15 00:00 [pubmed]
PHST- 1988/12/15 00:01 [medline]
PHST- 1988/12/15 00:00 [entrez]
PST - ppublish
SO  - Cancer Res. 1988 Dec 15;48(24 Pt 1):7022-32.