Plateau-phase cultures

an experimental model for identifying drugs which are bioactivated within the microenvironment of solid tumours

R M Phillips, M R Clayton

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

A commonly used technique for evaluating potential bioreductive drugs is the determination of hypoxic cytotoxicity ratios in vitro. This experimental model, however, does not accurately mimic the tumour microenvironment, as other factors (such as reduced pH, poor nutrient status, low cell proliferation rates and high catabolite concentrations) are not incorporated into the design of the assay. Plateau-phase monolayer cultures possess many of these characteristics, and this study compared the response of plateau-phase and exponentially growing human colon carcinoma cells (DLD-1) with a series of standard and bioreductive compounds. All drugs tested were added directly to conditioned medium and three patterns of chemosensitivity were observed. In the case of doxorubicin, vinblastine and 5-fluorouracil, exponentially growing cells were significantly more responsive than plateau-phase cultures. ThioTEPA and MeDZQ (2,5-diaziridinyl-1, 4-benzoquinone) were equally cytotoxic to both populations of cells. Tirapazamine (SR4233), RSU 1069, mitomycin C and EO-9, however, were preferentially toxic towards plateau-phase compared with exponentially growing cells. While the exact mechanisms responsible for these observations in each case are not known, this study suggests that plateau-phase cultures may prove to be a useful experimental model in the evaluation of drugs designed to work preferentially within the tumour microenvironment.

Original languageEnglish
Pages (from-to)196-201
Number of pages6
JournalBritish Journal of Cancer
Volume75
Issue number2
DOIs
Publication statusPublished - 1997
Externally publishedYes

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Tumor Microenvironment
Theoretical Models
tirapazamine
apaziquone
Pharmaceutical Preparations
Drug Evaluation
Vinblastine
Poisons
Mitomycin
Conditioned Culture Medium
Fluorouracil
Doxorubicin
Colon
Cell Proliferation
Carcinoma
Food
Population

Cite this

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title = "Plateau-phase cultures: an experimental model for identifying drugs which are bioactivated within the microenvironment of solid tumours",
abstract = "A commonly used technique for evaluating potential bioreductive drugs is the determination of hypoxic cytotoxicity ratios in vitro. This experimental model, however, does not accurately mimic the tumour microenvironment, as other factors (such as reduced pH, poor nutrient status, low cell proliferation rates and high catabolite concentrations) are not incorporated into the design of the assay. Plateau-phase monolayer cultures possess many of these characteristics, and this study compared the response of plateau-phase and exponentially growing human colon carcinoma cells (DLD-1) with a series of standard and bioreductive compounds. All drugs tested were added directly to conditioned medium and three patterns of chemosensitivity were observed. In the case of doxorubicin, vinblastine and 5-fluorouracil, exponentially growing cells were significantly more responsive than plateau-phase cultures. ThioTEPA and MeDZQ (2,5-diaziridinyl-1, 4-benzoquinone) were equally cytotoxic to both populations of cells. Tirapazamine (SR4233), RSU 1069, mitomycin C and EO-9, however, were preferentially toxic towards plateau-phase compared with exponentially growing cells. While the exact mechanisms responsible for these observations in each case are not known, this study suggests that plateau-phase cultures may prove to be a useful experimental model in the evaluation of drugs designed to work preferentially within the tumour microenvironment.",
keywords = "Antineoplastic Agents/administration & dosage, Carcinoma/pathology, Cell Division, Colonic Neoplasms/pathology, Humans, Hydrogen-Ion Concentration, Hypoxia, Prodrugs/metabolism, Tumor Cells, Cultured",
author = "Phillips, {R M} and Clayton, {M R}",
year = "1997",
doi = "10.1038/bjc.1997.33",
language = "English",
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pages = "196--201",
journal = "British Journal of Cancer",
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T2 - an experimental model for identifying drugs which are bioactivated within the microenvironment of solid tumours

AU - Phillips, R M

AU - Clayton, M R

PY - 1997

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N2 - A commonly used technique for evaluating potential bioreductive drugs is the determination of hypoxic cytotoxicity ratios in vitro. This experimental model, however, does not accurately mimic the tumour microenvironment, as other factors (such as reduced pH, poor nutrient status, low cell proliferation rates and high catabolite concentrations) are not incorporated into the design of the assay. Plateau-phase monolayer cultures possess many of these characteristics, and this study compared the response of plateau-phase and exponentially growing human colon carcinoma cells (DLD-1) with a series of standard and bioreductive compounds. All drugs tested were added directly to conditioned medium and three patterns of chemosensitivity were observed. In the case of doxorubicin, vinblastine and 5-fluorouracil, exponentially growing cells were significantly more responsive than plateau-phase cultures. ThioTEPA and MeDZQ (2,5-diaziridinyl-1, 4-benzoquinone) were equally cytotoxic to both populations of cells. Tirapazamine (SR4233), RSU 1069, mitomycin C and EO-9, however, were preferentially toxic towards plateau-phase compared with exponentially growing cells. While the exact mechanisms responsible for these observations in each case are not known, this study suggests that plateau-phase cultures may prove to be a useful experimental model in the evaluation of drugs designed to work preferentially within the tumour microenvironment.

AB - A commonly used technique for evaluating potential bioreductive drugs is the determination of hypoxic cytotoxicity ratios in vitro. This experimental model, however, does not accurately mimic the tumour microenvironment, as other factors (such as reduced pH, poor nutrient status, low cell proliferation rates and high catabolite concentrations) are not incorporated into the design of the assay. Plateau-phase monolayer cultures possess many of these characteristics, and this study compared the response of plateau-phase and exponentially growing human colon carcinoma cells (DLD-1) with a series of standard and bioreductive compounds. All drugs tested were added directly to conditioned medium and three patterns of chemosensitivity were observed. In the case of doxorubicin, vinblastine and 5-fluorouracil, exponentially growing cells were significantly more responsive than plateau-phase cultures. ThioTEPA and MeDZQ (2,5-diaziridinyl-1, 4-benzoquinone) were equally cytotoxic to both populations of cells. Tirapazamine (SR4233), RSU 1069, mitomycin C and EO-9, however, were preferentially toxic towards plateau-phase compared with exponentially growing cells. While the exact mechanisms responsible for these observations in each case are not known, this study suggests that plateau-phase cultures may prove to be a useful experimental model in the evaluation of drugs designed to work preferentially within the tumour microenvironment.

KW - Antineoplastic Agents/administration & dosage

KW - Carcinoma/pathology

KW - Cell Division

KW - Colonic Neoplasms/pathology

KW - Humans

KW - Hydrogen-Ion Concentration

KW - Hypoxia

KW - Prodrugs/metabolism

KW - Tumor Cells, Cultured

U2 - 10.1038/bjc.1997.33

DO - 10.1038/bjc.1997.33

M3 - Article

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JF - British Journal of Cancer

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