Multicellular resistance to tirapazamine is due to restricted extravascular transport: a pharmacokinetic/pharmacodynamic study in HT29 multicellular layer cultures.
نویسندگان
چکیده
In common with other bioreductive drugs, metabolic reduction is required for activation of the benzotriazine-di-N-oxide tirapazamine (TPZ) in hypoxic regions of tumors. This same metabolism also consumes the drug as it diffuses, impeding its penetration into hypoxic tissue. In this study, we develop a pharmacokinetic (PK)/pharmacodynamic (PD) model for TPZ that explicitly includes its diffusion characteristics as measured in multicellular layer (MCL) cultures of HT29 colon carcinoma cells. The kinetics of TPZ metabolism to its mono-N-oxide derivative SR 4317, determined by high-performance liquid chromatography using anoxic HT29 single cell suspensions, demonstrated both a first order and saturable (K(m) = 3.6 micro M) component. Cell killing, assessed by clonogenic assay under the same conditions, demonstrated an approximately quadratic concentration dependence and linear time dependence. TPZ transport through MCLs, determined under hyperoxic conditions (95% O(2)) to suppress reductive metabolism, provided a concentration-independent diffusion coefficient of 0.40 x 10(-6) cm(2)s(-1). Under anoxia, this transport was strongly suppressed and was well predicted by the single cell metabolism parameters (scaled to the cell density in MCLs). These PK (transport) and PD (cytotoxicity) parameters were used to calculate cell killing as a function of distance in anoxic HT29 MCLs after the addition of TPZ to both sides of the MCL. The predicted average cell kill was in good agreement with measured values, which showed much less killing than for single cell suspensions under the same conditions. The success of this PK/PD model in predicting response in MCL shows that inefficient transport, rather than changes in intrinsic sensitivity, is responsible for TPZ resistance in these three-dimensional cell cultures and suggests that optimization of transport properties is a high priority in developing second-generation TPZ analogues.
منابع مشابه
Pharmacokinetic/pharmacodynamic modeling identifies SN30000 and SN29751 as tirapazamine analogues with improved tissue penetration and hypoxic cell killing in tumors.
PURPOSE Tirapazamine (TPZ) has attractive features for targeting hypoxic cells in tumors but has limited clinical activity, in part because of poor extravascular penetration. Here, we identify improved TPZ analogues by using a spatially resolved pharmacokinetic/pharmacodynamic (SR-PKPD) model that considers tissue penetration explicitly during lead optimization. EXPERIMENTAL DESIGN The SR-PKP...
متن کاملrmacokinetic/Pharmacodynamic Modeling Identifies 0000 and SN29751 as Tirapazamine Analogues with roved Tissue Penetration and Hypoxic R l Killing in Tumors
wnloaded pose: Tirapazamine (TPZ) has attractive features for targeting hypoxic cells in tumors but has limlinical activity, in part because of poor extravascular penetration. Here, we identify improved TPZ gues by using a spatially resolved pharmacokinetic/pharmacodynamic (SR-PKPD) model that contissue penetration explicitly during lead optimization. erimental design: The SR-PKPD model was use...
متن کاملSelective potentiation of the hypoxic cytotoxicity of tirapazamine by its 1-N-oxide metabolite SR 4317.
Tirapazamine (TPZ), a bioreductive drug with selective toxicity for hypoxic cells in tumors, is currently in Phase III clinical trials. It has been suggested to have a dual mechanism of action, both generating DNA radicals and oxidizing these radicals to form DNA breaks; whether the second (radical oxidation) step is rate-limiting in cells is not known. In this study we exploit the DNA radical ...
متن کاملMicrodosimetry study of a multicellular model with mono-energetic electrons using Geant4-DNA simulation toolkit
Introduction: The goal of any type of radiation therapy in the treatment of tumors, in addition to destroying cancer cells, is to minimizing radiation to nearby healthy cells and thus reducing side damages. For this purpose, targeted radiation therapy (TRT) is more effective in treating of single cells or small cluster of cells. The main factor in the success of this method is...
متن کاملAntiadhesive antibodies targeting E-cadherin sensitize multicellular tumor spheroids to chemotherapy in vitro.
Multicellular resistance, a subtype of therapeutic resistance manifested in cancer cells grown as three-dimensional multicellular masses, such as spheroids in vitro and solid tumors in vivo, occurs with respect to a variety of anticancer treatment strategies including chemotherapy, ionizing radiation, and even host-mediated antibody-dependent cellular cytotoxicity. Previous studies from our lab...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Cancer research
دوره 63 18 شماره
صفحات -
تاریخ انتشار 2003