Concurrent measurements of blood flow and transcapillary transport in avian sarcoma virus-induced experimental brian tumors

Implications for chemotherapy

R. Blasberg, P. Molnár, D. Groothius, C. Patlak, E. Owens, J. Fenstermacher

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

A blood-to-tissue transfer constant, K, and tissue blood flow, F, were measured concurrently in seven rats with a total of 19 separate brain tumors induced by intracerebral inoculation of avian sarcoma virus. Regional and local measurements of K and F were obtained using double-label quantitative autoradiography with α-[14C]aminoisobutyric acid and [131I]iodoantipyrine, computerized microdensitometry and image analysis. Apparent tissue extraction fractions and capillary permeability-surface area products were calculated for different tumor regions, brain adjacent to tumor and tumor-free brain. The following observations were made: 1) five histological categories of the tumors were found; 2) significant local and regional variations of both K and F were typical in each group, resulting in marked regional variability of permeability-surface area products but more uniform values of apparent extraction fraction; 3) the values of F, K, permeability-surface area products and apparent extraction fraction correlated poorly with morphological features of the tumors (necrosis, cellularity, cytology, location and size); 4) the extraction fraction of α-aminoisobutyric acid was usually highest in tumor centers and then decreased in a gradient from tumor periphery through adjacent brain; and 5) regardless of classification or histological features, capillary permeability and surface area, and not tissue perfusion or blood flow, seem to determine the blood-to-tissue transport processes (delivery of bloodborne materials) in most regions of these experimental brain tumors. An operational pharmacokinetic model of drug concentration in tumor tissue is developed and the results of our analysis indicate that increases in capillary permeability such as measured in these studies would not be sufficient to deliver adequate amounts of water-soluble drugs with short plasma half-lives to tumor tissue.

Original languageEnglish
Pages (from-to)724-735
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume231
Issue number3
Publication statusPublished - 1984

Fingerprint

Avian Sarcoma Viruses
Drug Therapy
Brain Neoplasms
Capillary Permeability
Neoplasms
Aminoisobutyric Acids
Permeability
Autoradiography
Pharmaceutical Preparations
Cell Biology
Necrosis
Pharmacokinetics
Perfusion
Water
Brain

ASJC Scopus subject areas

  • Pharmacology

Cite this

Concurrent measurements of blood flow and transcapillary transport in avian sarcoma virus-induced experimental brian tumors : Implications for chemotherapy. / Blasberg, R.; Molnár, P.; Groothius, D.; Patlak, C.; Owens, E.; Fenstermacher, J.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 231, No. 3, 1984, p. 724-735.

Research output: Contribution to journalArticle

@article{fe963e17fdc64c1f8010c4c129d6356d,
title = "Concurrent measurements of blood flow and transcapillary transport in avian sarcoma virus-induced experimental brian tumors: Implications for chemotherapy",
abstract = "A blood-to-tissue transfer constant, K, and tissue blood flow, F, were measured concurrently in seven rats with a total of 19 separate brain tumors induced by intracerebral inoculation of avian sarcoma virus. Regional and local measurements of K and F were obtained using double-label quantitative autoradiography with α-[14C]aminoisobutyric acid and [131I]iodoantipyrine, computerized microdensitometry and image analysis. Apparent tissue extraction fractions and capillary permeability-surface area products were calculated for different tumor regions, brain adjacent to tumor and tumor-free brain. The following observations were made: 1) five histological categories of the tumors were found; 2) significant local and regional variations of both K and F were typical in each group, resulting in marked regional variability of permeability-surface area products but more uniform values of apparent extraction fraction; 3) the values of F, K, permeability-surface area products and apparent extraction fraction correlated poorly with morphological features of the tumors (necrosis, cellularity, cytology, location and size); 4) the extraction fraction of α-aminoisobutyric acid was usually highest in tumor centers and then decreased in a gradient from tumor periphery through adjacent brain; and 5) regardless of classification or histological features, capillary permeability and surface area, and not tissue perfusion or blood flow, seem to determine the blood-to-tissue transport processes (delivery of bloodborne materials) in most regions of these experimental brain tumors. An operational pharmacokinetic model of drug concentration in tumor tissue is developed and the results of our analysis indicate that increases in capillary permeability such as measured in these studies would not be sufficient to deliver adequate amounts of water-soluble drugs with short plasma half-lives to tumor tissue.",
author = "R. Blasberg and P. Moln{\'a}r and D. Groothius and C. Patlak and E. Owens and J. Fenstermacher",
year = "1984",
language = "English",
volume = "231",
pages = "724--735",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - Concurrent measurements of blood flow and transcapillary transport in avian sarcoma virus-induced experimental brian tumors

T2 - Implications for chemotherapy

AU - Blasberg, R.

AU - Molnár, P.

AU - Groothius, D.

AU - Patlak, C.

AU - Owens, E.

AU - Fenstermacher, J.

PY - 1984

Y1 - 1984

N2 - A blood-to-tissue transfer constant, K, and tissue blood flow, F, were measured concurrently in seven rats with a total of 19 separate brain tumors induced by intracerebral inoculation of avian sarcoma virus. Regional and local measurements of K and F were obtained using double-label quantitative autoradiography with α-[14C]aminoisobutyric acid and [131I]iodoantipyrine, computerized microdensitometry and image analysis. Apparent tissue extraction fractions and capillary permeability-surface area products were calculated for different tumor regions, brain adjacent to tumor and tumor-free brain. The following observations were made: 1) five histological categories of the tumors were found; 2) significant local and regional variations of both K and F were typical in each group, resulting in marked regional variability of permeability-surface area products but more uniform values of apparent extraction fraction; 3) the values of F, K, permeability-surface area products and apparent extraction fraction correlated poorly with morphological features of the tumors (necrosis, cellularity, cytology, location and size); 4) the extraction fraction of α-aminoisobutyric acid was usually highest in tumor centers and then decreased in a gradient from tumor periphery through adjacent brain; and 5) regardless of classification or histological features, capillary permeability and surface area, and not tissue perfusion or blood flow, seem to determine the blood-to-tissue transport processes (delivery of bloodborne materials) in most regions of these experimental brain tumors. An operational pharmacokinetic model of drug concentration in tumor tissue is developed and the results of our analysis indicate that increases in capillary permeability such as measured in these studies would not be sufficient to deliver adequate amounts of water-soluble drugs with short plasma half-lives to tumor tissue.

AB - A blood-to-tissue transfer constant, K, and tissue blood flow, F, were measured concurrently in seven rats with a total of 19 separate brain tumors induced by intracerebral inoculation of avian sarcoma virus. Regional and local measurements of K and F were obtained using double-label quantitative autoradiography with α-[14C]aminoisobutyric acid and [131I]iodoantipyrine, computerized microdensitometry and image analysis. Apparent tissue extraction fractions and capillary permeability-surface area products were calculated for different tumor regions, brain adjacent to tumor and tumor-free brain. The following observations were made: 1) five histological categories of the tumors were found; 2) significant local and regional variations of both K and F were typical in each group, resulting in marked regional variability of permeability-surface area products but more uniform values of apparent extraction fraction; 3) the values of F, K, permeability-surface area products and apparent extraction fraction correlated poorly with morphological features of the tumors (necrosis, cellularity, cytology, location and size); 4) the extraction fraction of α-aminoisobutyric acid was usually highest in tumor centers and then decreased in a gradient from tumor periphery through adjacent brain; and 5) regardless of classification or histological features, capillary permeability and surface area, and not tissue perfusion or blood flow, seem to determine the blood-to-tissue transport processes (delivery of bloodborne materials) in most regions of these experimental brain tumors. An operational pharmacokinetic model of drug concentration in tumor tissue is developed and the results of our analysis indicate that increases in capillary permeability such as measured in these studies would not be sufficient to deliver adequate amounts of water-soluble drugs with short plasma half-lives to tumor tissue.

UR - http://www.scopus.com/inward/record.url?scp=0021739373&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0021739373&partnerID=8YFLogxK

M3 - Article

VL - 231

SP - 724

EP - 735

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -