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  • Review Article
  • Published:

Drug penetration in solid tumours

Nature Reviews Cancer volume 6, pages 583–592 (2006)Cite this article

Key Points

  • Most studies of tumour resistance to anticancer drugs consider only cellular and/or genetic causes operative at the level of a single cell.

  • Many anticancer drugs have limited distribution from blood vessels in solid tumours, which limits their effectiveness.

  • Large distances between blood vessels in solid tumours, the composition of the extracellular matrix, cell–cell adhesion, high interstitial fluid pressure, lack of convection, drug metabolism and binding contribute to limited drug distribution.

  • New in vitro and in vivo techniques enable quantitative assessment of drug penetration.

  • Several strategies have the potential to improve the distribution of anticancer drugs in tumours, and thereby improve their therapeutic index.

  • Drug development strategies where molecules are designed or libraries screened for optimal drug penetration would aid the development of more effective anticancer drugs.

Abstract

To be most effective anticancer drugs must penetrate tissue efficiently, reaching all the cancer cells that comprise the target population in a concentration sufficient to exert a therapeutic effect. Most research into the resistance of cancers to chemotherapy has concentrated on molecular mechanisms of resistance, whereas the role of limited drug distribution within tumours has been neglected. We summarize the evidence that indicates that the distribution of many anticancer drugs in tumour tissue is incomplete, and we suggest strategies that might be used either to improve drug penetration through tumour tissue or to select compounds based on their abilities to penetrate tissue, thereby increasing the therapeutic index.

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Figure 1: Potential reasons why cells distant from blood vessels might be resistant to treatment.
Figure 2: Drug distribution in tissue.
Figure 3: Multicellular models and their use to study drug penetration.
Figure 4: Distribution of doxorubicin in vivo
Figure 5: Tissue mapping of a human colorectal cancer xenograft.

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Acknowledgements

We thank R. K. Jain and W. R. Wilson for their constructive review of an earlier version of this paper.

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Authors and Affiliations

  1. Department of Medical Biophysics, British Columbia Cancer Research Centre, Vancouver, Canada

    Andrew I. Minchinton

  2. Departments of Medical Biophysics and Medical Oncology and Haematology, Princess Margaret Hospital and University of Toronto, Toronto, Canada

    Ian F. Tannock

Authors
  1. Andrew I. Minchinton
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  2. Ian F. Tannock
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Corresponding authors

Correspondence to Andrew I. Minchinton or Ian F. Tannock.

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Competing interests

Andrew Minchinton holds a patent, and has a patent pending, for techniques that measure extravascular drug penetration. And holds equity in Cabenda Pharmaceutical Research Ltd, a drug development and research company that measures the tissue penetration of drugs.

Ian Tannock receives research funding from Novacea, for studies of their experimental drug AQ4N.

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DATABASES

National Cancer Institute

breast cancer

colon cancer

FURTHER INFORMATION

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Glossary

Interstitial fluid pressure

The hydrostatic pressure within the interstitial fluid of solid tissue. In tumours, disordered vasculature and the absence of functioning lymphatics is associated with increased interstitial fluid pressure compared with normal tissues.

Extracellular matrix

The complex group of molecules that exist in tissue outside cells.

Clonogenic cell

A cell with the ability to generate progeny that will form a colony of a predetermined minimum size when placed under appropriate conditions. Such cells might represent tumour stem cells, which can regenerate a tumour after treatment.

Tumour stem cell

A tumour cell that has the capacity to regenerate the tumour after treatment. Such cells must be eradicated if tumour therapy is to be curative. Stem cells in some tumours can have surface markers that facilitate their identification.

Pharmacokinetics

The time course of drug absorption, distribution, metabolism and excretion within the body.

Volume of distribution

A hypothetical volume calculated by extrapolating the plasma concentration–time curve back to time zero, which represents the volume at which the administered drug seems to have been distributed. Large volumes of distribution imply efficient extravasation, but not necessarily complete distribution in tumour tissue.

Spheroids

Spherical aggregates of tumour cells, grown in tissue culture, which reflect many of the properties of solid tumours. Spheroids have been used for studying the penetration of anticancer drugs into tumour tissue.

Cell contact effect

The growth of tumour cells that are in contact with each other leads to changes in the expression of some genes, and has been shown to influence cellular properties, including response to therapeutic agents, compared with single cells in culture.

Multilayered cell culture

Also called a multicellular layer or a multicellular membrane,anMCC contains tumour cells that grow on a permeable plastic support membrane to form a disc of tissue.MCCsreflect many of the properties of solid tumours, and are used to study the penetration of anticancer drugs through tumour tissue.

Pharmacodynamics

The effects of a drug on the cells and tissues of the body.

Partition coefficient

The ratio of the solubility of a drug in two solvents, usually octanol and water. The logarithm of this number (logP) is commonly used to describe relative hydrophobicity or hydrophilicity.

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Minchinton, A., Tannock, I. Drug penetration in solid tumours. Nat Rev Cancer 6, 583–592 (2006). https://doi.org/10.1038/nrc1893

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