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Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs.

Publication ,  Journal Article
Hicks, KO; Pruijn, FB; Secomb, TW; Hay, MP; Hsu, R; Brown, JM; Denny, WA; Dewhirst, MW; Wilson, WR
Published in: J Natl Cancer Inst
August 16, 2006

BACKGROUND: Because of the inefficient vasculature of solid tumors, anticancer drugs must penetrate relatively long distances through the extravascular compartment. The requirement for such diffusion may limit their activity, especially that of hypoxia-targeted drugs. We tested whether a three-dimensional pharmacokinetic/pharmacodynamic (PK/PD) model based on a representative mapped tumor microvascular network could predict the therapeutic activity of anticancer drugs in mouse xenograft tumors. METHODS: Diffusion coefficients of the hypoxia-activated anticancer drug tirapazamine (TPZ) and of 15 TPZ analogs were estimated by measuring their transport through HT29 colon cancer multicellular layers (MCLs). Anoxic cytotoxic potency (by clonogenic assay) and metabolism of the TPZ analogs were measured in HT29 cell suspensions, and their plasma pharmacokinetics was measured in CD-1 nude mice. This information was used to create a spatially resolved PK/PD model for the tumor microvascular network. Model predictions were compared with actual hypoxic cell kill as measured by clonogenic assays on HT29 xenograft tumors 18 hours after treatment with each TPZ analog. RESULTS: Modeling TPZ transport in the tumor microvascular network showed substantial drug depletion in the most hypoxic regions, with predicted maximum cell kill of only 3 logs, compared with more than 10 logs if there were no transport impediment. A large range of tissue diffusion coefficients (0.027 x 10(-6)-1.87 x 10(-6) cm2/s) was observed for the TPZ analogs. There was a strong correlation between model-predicted and measured hypoxic cell kill (R2 = 0.89) but a poor correlation when the model did not include extravascular transport (R2 = 0.32). CONCLUSIONS: Extravascular transport in tumors, and its consequences for tumor cell killing, can be predicted by measuring drug penetration through MCLs in vitro and modeling pharmacokinetics at each position in three-dimensional microvascular networks.

Duke Scholars

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Published In

J Natl Cancer Inst

DOI

EISSN

1460-2105

Publication Date

August 16, 2006

Volume

98

Issue

16

Start / End Page

1118 / 1128

Location

United States

Related Subject Headings

  • Tumor Stem Cell Assay
  • Tumor Cells, Cultured
  • Triazines
  • Transplantation, Heterologous
  • Tirapazamine
  • Reproducibility of Results
  • Radiation-Sensitizing Agents
  • Oncology & Carcinogenesis
  • Mice
  • Hypoxia
 

Citation

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Hicks, K. O., Pruijn, F. B., Secomb, T. W., Hay, M. P., Hsu, R., Brown, J. M., … Wilson, W. R. (2006). Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs. J Natl Cancer Inst, 98(16), 1118–1128. https://doi.org/10.1093/jnci/djj306
Hicks, Kevin O., Frederik B. Pruijn, Timothy W. Secomb, Michael P. Hay, Richard Hsu, J Martin Brown, William A. Denny, Mark W. Dewhirst, and William R. Wilson. “Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs.J Natl Cancer Inst 98, no. 16 (August 16, 2006): 1118–28. https://doi.org/10.1093/jnci/djj306.
Hicks KO, Pruijn FB, Secomb TW, Hay MP, Hsu R, Brown JM, et al. Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs. J Natl Cancer Inst. 2006 Aug 16;98(16):1118–28.
Hicks, Kevin O., et al. “Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs.J Natl Cancer Inst, vol. 98, no. 16, Aug. 2006, pp. 1118–28. Pubmed, doi:10.1093/jnci/djj306.
Hicks KO, Pruijn FB, Secomb TW, Hay MP, Hsu R, Brown JM, Denny WA, Dewhirst MW, Wilson WR. Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs. J Natl Cancer Inst. 2006 Aug 16;98(16):1118–1128.
Journal cover image

Published In

J Natl Cancer Inst

DOI

EISSN

1460-2105

Publication Date

August 16, 2006

Volume

98

Issue

16

Start / End Page

1118 / 1128

Location

United States

Related Subject Headings

  • Tumor Stem Cell Assay
  • Tumor Cells, Cultured
  • Triazines
  • Transplantation, Heterologous
  • Tirapazamine
  • Reproducibility of Results
  • Radiation-Sensitizing Agents
  • Oncology & Carcinogenesis
  • Mice
  • Hypoxia