Register      Login
Australian Journal of Chemistry Australian Journal of Chemistry Society
An international journal for chemical science
Shopping Cart: ( empty )
You are here: Home > Journals > CH > CH08240
RESEARCH FRONT (Open Access)
Contents Vol 61(9)

Prediction of Tumour Tissue Diffusion Coefficients of Hypoxia-Activated Prodrugs from Physicochemical Parameters

Frederik B. Pruijn A B , Kashyap Patel A , Michael P. Hay A , William R. Wilson A and Kevin O. Hicks A
+ Author Affiliations
- Author Affiliations

A Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

B Corresponding author. Email: f.pruijn@auckland.ac.nz

Australian Journal of Chemistry 61(9) 687-693 https://doi.org/10.1071/CH08240
Submitted: 5 June 2008  Accepted: 9 July 2008   Published: 5 September 2008

Abstract

The therapeutic activity of anticancer agents depends critically on their ability to penetrate through tumour tissue to reach their target cells, a requirement that is especially important for hypoxia-activated prodrugs. Here we use multicellular layers (MCL) grown in vitro from HT29 colon carcinoma cells to measure tissue diffusion coefficients (Dmcl) of 67 structurally diverse benzotriazine di-N-oxides (analogues of the hypoxia-activated prodrug tirapazamine) plus four miscellaneous compounds. An algorithm was developed to predict Dmcl from physicochemical parameters (molecular weight, octanol/water partition coefficient at pH 7.4, number of hydrogen bond donors and acceptors); the fitted multivariate relationship had an explained variance (R2) of 0.907 and predictive power (Q2) of 0.879. Using a subset of nine compounds tested as a single cassette, the algorithm was shown to apply, with some adjustment of coefficients, to MCLs from three other tumour cell lines with differing cell packing densities (SiHa, HCT8-Ea, and HCT8-Ra). The demonstrated relationships provide tools for optimizing extravascular transport of anticancer agents during lead optimization.


Acknowledgements

The authors thank Joanna Sturman and Rachel Chapman for excellent assistance with the MCL flux experiments and Sarath Liyanage for log P7.4 measurements. This study was supported by Grant No. CA82566 from the USA National Cancer Institute, and the Health Research Council of New Zealand.


References


[1]   Vaupel P., Kelleher D. K. (Eds), Tumor Hypoxia: Pathophysiology, Clinical Significance and Therapeutic Perspectives 1999 (Wissenschaftliche Verlagsgesellschaft mbH: Stuttgart).

[2]   J. L. Tatum, G. J. Kelloff, R. J. Gillies, J. M. Arbeit, J. M. Brown, K. S. Chao, J. D. Chapman, W. C. Eckelman, A.W. Fyles, A. J. Giaccia, R. P. Hill, C. J. Koch, M. C. Krishna, K. A. Krohn, J. S. Lewis, R. P. Mason, G. Melillo, A. R. Padhani, G. Powis, J. G. Rajendran, R. Reba, S. P. Robinson, G. L. Semenza, H. M. Swartz, P. Vaupel, D. Yang, B. Croft, J. Hoffman, G. Liu, H. Stone, D. Sullivan, Int. J. Radiat. Biol. 2006, 82,  699.
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        |  CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
         
        |  CAS |  
        |  CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        |  CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        |  CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        |  CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        |  CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        |  CAS |  
        |  CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        |  CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
         
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        |  CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        |  CAS |  
        |  CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        |  CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  
        | Crossref |  GoogleScholarGoogle Scholar | CAS |  open url image1