TY - JOUR
T1 - Prediction of tumour tissue diffusion coefficients of hypoxia-activated prodrugs from physicochemical parameters
AU - Pruijn, Frederik B
AU - Patel, Kashyap
AU - Hay, Michael P
AU - Wilson, William Robert
AU - Hicks, Kevin O
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
UR - http://www.publish.csiro.au/?act=view_file&file_id=CH08240.pdf
U2 - 10.1071/CH08240
DO - 10.1071/CH08240
M3 - Article
VL - 61
SP - 687
EP - 693
JO - Australian Journal of Chemistry
JF - Australian Journal of Chemistry
SN - 0004-9425
IS - 9
ER -