Auckland Cancer Society Research Centre

Extravascular transport of anticancer agents

Project leaders

Research overview


Drugs that kill cancer cells (cytotoxic drugs) must reach their target cells in order to be effective. It is now clear that poor drug transport in tumours can be a major cause of resistance to chemotherapy. Drug transport in tumours has been studied primarily using window chambers in vivo and multicellular spheroids in vitro.

Read more about Drug transport

Our group has broad interests in the use of three dimensional cell cultures in drug development and has developed multicellular layers as a new technique to study the drug transport problem. Multicellular layers consist of cells grown in tissue culture inserts. Growing submerged in culture medium allows them to reach 100-200 um in thickness within 3-5 days, after which they begin to develop central necrosis. In this way they are a model of the extravascular compartment of solid tumours.

Drug transport is studied using MCL in diffusion chambers. Drug is added to one side (donor compartment) and samples are taken at time intervals from both the donor and receiver compartments. These samples are analysed by sensitive analytical methods such as liquid chromatography and mass spectrometry (LCMS). The concentrations of drug can then be used to estimate the rates of drug diffusion and drug metabolism which are critical in predicting the concentrations of drugs in tumours.

Drug transport studies such as these have been used to guide the development of tirapazamine analogs with better tumour penetration and to develop predictive transport models for PR104 and related hypoxia activated dinitrobenzamide mustard prodrugs and hypoxia-activated prodrugs of DNA minor groove alkylating agents. Large numbers of drugs have now been tested allowing us to develop a tools to predict the diffusion coefficients of related compounds in silico.

Tirapazamine analogs

Predictive transport models

PR104 and related hypoxia activated dinitrobenzamide mustard prodrugs

Hypoxia-activated prodrugs of DNA minor groove alkylating agents

MCL are also ideal for co-culturing cells, some of which activate prodrugs, to investigate the diffusion of locally produced (bystander) cytotoxins. This has been used extensively in the development of the dinitrobenzamide mustard prodrugs Dru.

Drug transport is an integral part of most research in the ETG. Some staff and students specifically involved are:

Selected publications on drug transport

Pruijn FB, Patel K, Hay MP, Wilson WR, Hicks KO (2008) Prediction of tumour tissue diffusion coefficients of hypoxia-activated prodrugs from physicochemical parameters. Aust J Chem 61: 687-693.  effects of bioreductive drugs: potential for exploiting pathological tumor hypoxia with dinitrobenzamide mustards. Radiat Res 167: 625-636. 

Hicks KO, Myint H, Patterson AV, Pruijn FB, Siim BG, Patel K, Wilson WR (2007) Oxygen dependence and extravascular transport of hypoxia-activated prodrugs: comparison of the dinitrobenzamide mustard PR-104A and tirapazamine. Int J Radiat Oncol Biol Phys 69: 560-571.

Hicks, KO, Pruijn, FB, Secomb, TW, Hay, MP, Hsu, R, Brown, JM, Denny, WA, Dewhirst, MW, 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. 

Pruijn, FB, Sturman, J, Liyanage, S, Hicks, KO, Hay, MP, Wilson, WR (2005) Extravascular transport of drugs in tumor tissue: Effect of lipophilicity on diffusion of tirapazamine analogues in multicellular layer cultures. J. Med. Chem. 48, 1079–1087.

Wilson WR, Pullen SM, Hogg A, Hobbs SM, Pruijn FB, Hicks KO (2004) In vitro and in vivo models for evaluation of GDEPT: quantifying bystander killing in cell cultures and tumors. Methods Mol Med 90: 403-431.

Hicks, KO, Siim BG, Pruijn FB, Wilson, WR (2004) Oxygen dependence of the metabolic activation and cytotoxicity of tirapazamine: implications for extravascular transport and activity in tumors. Radiat Res. 161, 656-66. 

Hicks, KO, Pruijn, FB, Sturman, JR, Denny, WA, Wilson, WR (2003) Multicellular resistance to tirapazamine is due to restricted extravascular transport: a pharmacokinetic/pharmacodynamic study in HT29 multicellular layer cultures. Cancer Res., 63, 5970-7. 

Wilson, WR, Pullen, SM, Hogg, A, Helsby, NA, Hicks, KO, Denny, WA (2002) Quantitation of bystander effects in nitroreductase suicide gene therapy using three-dimensional cell cultures . Cancer Res. 62 (5):1425-1432,. 

Hicks, KO, Pruijn, FB, Baguley, BC, Wilson, WR (2001) Extravascular transport of the DNA intercalator and topoisomerase poison N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA): diffusion and metabolism in multicellular layers of tumor cells. J Pharmacol Exp Ther., 297, 1088-98. 

Wilson, WR and Hicks, KO (1999) Measurement of extravascular drug diffusion in multicellular layers. Br.J.Cancer 79 (9-10):1623-1626.

Hicks, KO, Fleming, Y, Siim, BG, Koch, CJ, Wilson, WR (1998) Extravascular diffusion of tirapazamine: effect of metabolic consumption assessed using the multicellular layer model. Int J Radiat Oncol Biol Phys, 42, 641-9. 

Hicks, KO, Ohms, SJ, van Zijl, PL, Denny, WA, Hunter, PJ, Wilson, WR (1997) An experimental and mathematical model for the extravascular transport of a DNA intercalator in tumours. Br J Cancer, 76, 894-903.

Cowan DS, Hicks KO, Wilson WR (1996) Multicellular membranes as an in vitro model for extravascular diffusion in tumours. Br J Cancer Suppl 27: S28-S31 

Book chapters

Hicks KO. (2008) Three-Dimensional Tissue Cultures. In: Schwab M, editor. Encyclopedia of Cancer. Berlin Heidelberg New York: Springer-Verlag ;. p. 2956-61.

Wilson WR, Hicks KO, Pruijn FB, Patterson AV. (2008) Targeting Tumor Hypoxia with Prodrugs: Challenges and Opportunities. Am. Assoc. Cancer Res. Educ. Book. 2008 ed. p. 293-310.

Wilson, WR, Pullen, SM, Hogg, A, Hobbs, SM, Pruijn, FB, Hicks, KO (2003) In vitro and in vivo models for evaluation of GDEPT: quantifying bystander killing in cell cultures and tumors. In: Springer CJ, editor. Suicide Gene Therapy: Methods and Reviews. Totowa: Humana Press, 2003. p. 403-32.

Baguley BC, Hicks KO, Wilson WR (2002) Tumour cell cultures in drug development. In: Baguley BC, Kerr DJ, editors. Anticancer Drug Development. San Diego: Academic Press;. p. 269-84.