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Martin J Brown - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetic pharmacodynamic modeling identifies sn30000 and sn29751 as tirapazamine analogues with improved tissue penetration and Hypoxic Cell killing in tumors
Clinical Cancer Research, 2010Co-Authors: Kevin O Hicks, Bronwyn G. Siim, Alison Hogg, Frederik B. Pruijn, Rita Patel, Jagdish K Jaiswal, Annie M Fraser, H Sarath D Liyanage, Mary Jo Dorie, Martin J BrownAbstract: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-PKPD model was used to guide the progression of 281 TPZ analogues through a hierarchical screen. For compounds exceeding Hypoxic selectivity thresholds in single-Cell cultures, SR-PKPD model parameters (kinetics of bioreductive metabolism, clonogenic Cell killing potency, diffusion coefficients in multiCellular layers, and plasma pharmacokinetics at well tolerated doses in mice) were measured to prioritize testing in xenograft models in combination with radiation. Results: SR-PKPD–guided lead optimization identified SN29751 and SN30000 as the most promising Hypoxic cytotoxins from two different structural subseries. Both were reduced to the corresponding 1-oxide selectively under hypoxia by HT29 Cells, with an oxygen dependence quantitatively similar to that of TPZ. SN30000, in particular, showed higher Hypoxic potency and selectivity than TPZ in tumor Cell cultures and faster diffusion through HT29 and SiHa multiCellular layers. Both compounds also provided superior plasma PK in mice and rats at equivalent toxicity. In agreement with SR-PKPD predictions, both were more active than TPZ with single dose or fractionated radiation against multiple human tumor xenografts. Conclusions: SN30000 and SN29751 are improved TPZ analogues with potential for targeting tumor hypoxia in humans. Novel SR-PKPD modeling approaches can be used for lead optimization during anticancer drug development. Clin Cancer Res; 16(20); 4946–57. ©2010 AACR.
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stereotactic ablative radiotherapy should be combined with a Hypoxic Cell radiosensitizer
International Journal of Radiation Oncology Biology Physics, 2010Co-Authors: Martin J Brown, Maximilian Diehn, Billy W LooAbstract:Purpose To evaluate the effect of tumor hypoxia on the expected level of Cell killing by regimens of stereotactic ablative radiotherapy (SABR) and to determine the extent to which the negative effect of hypoxia could be prevented using a clinically available Hypoxic Cell radiosensitizer. Results and Discussion We have calculated the expected level of tumor Cell killing from regimens of SABR, both with and without the assumption that 20% of the tumor Cells are Hypoxic, using the standard linear quadratic model and the universal survival curve modification. We compare the results obtained with our own clinical data for lung tumors of different sizes and with published data from other studies. We also have calculated the expected effect on Cell survival of adding the Hypoxic Cell sensitizer etanidazole at clinically achievable drug concentrations. Modeling tumor Cell killing with any of the currently used regimens of SABR produces results that are inconsistent with the majority of clinical findings if tumor hypoxia is not considered. However, with the assumption of tumor hypoxia, the expected level of Cell killing is consistent with clinical data. For only some of the smallest tumors are the clinical data consistent with no tumor hypoxia, but there could be other reasons for the sensitivity of these tumors. The addition of etanidazole at clinically achievable tumor concentrations produces a large increase in the expected level of tumor Cell killing from the large radiation doses used in SABR. Conclusions The presence of tumor hypoxia is a major negative factor in limiting the curability of tumors by SABR at radiation doses that are tolerable to surrounding normal tissues. However, this negative effect of hypoxia could be overcome by the addition of clinically tolerable doses of the Hypoxic Cell radiosensitizer etanidazole.
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characterization of a cho Cell line resistant to killing by the Hypoxic Cell cytotoxin sr 4233
International Journal of Radiation Oncology Biology Physics, 1992Co-Authors: Amato J Giaccia, Andrew I Minchinton, Kim A Biedermann, L Tosto, Mary S Kovacs, Martin J BrownAbstract:Abstract One approach to understanding the mechanism of selective Hypoxic Cell killing by the benzotriazine-di- N -oxide, SR 4233, is to characterize Cell lines that exhibit increased resistance to killing by this drug. The Chinese Hamster Ovary Cell line BL-10 was originally isolated on the basis of its hypersensitivity to killing by bleomycin. It is 2.7-fold more resistant to Hypoxic Cell killing by SR 4233 than wild-type CHO on comparison of Do's. However, both BL-10 and CHO possess the same sensitivity to killing by SR 4233 under aerobic conditions. We have excluded the explanation that differential metabolism of SR 4233 is responsible for its increased survival as both BL-10 and CHO produce the two-electron product SR 4317 at the same rate (3 nmoles/hr/106 Cells). Analysis of free radical production, DNA double-strand break induction, and glutathione (GSH) levels suggested that the resistance of BL-10 to killing by SR 4233 might result from increased intraCellular radical scavenger pathways. Using buthionine sulfoximine (BSO) to decrease Cellular GSH levels, we found a marked increase in the sensitivity of BL-10 Cells to SR 4233 killing under hypoxia, but a much smaller increase in the sensitivity of CHO Cells. Taken together, these data imply that the high GSH levels in BL-10 Cells is responsible for its resistance to SR 4233 cytotoxicity.
Seiichi Nishimoto - One of the best experts on this subject based on the ideXlab platform.
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propargylic sulfones possessing a 2 nitroimidazole function novel Hypoxic Cell radiosensitizers with intraCellular non protein thiol depletion ability
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Kazuhito Tanabe, Ryusuke Kojima, Hiroshi Hatta, Seiichi NishimotoAbstract:Abstract Propargylic sulfones ( 1a – c ) containing a 2-nitroimidazole structure were synthesized, and their non-protein thiol (NPSH) depletion abilities were investigated. Propargylic sulfones 1a , c containing an electron withdrawing p -nitrophenyl group showed high reactivity toward capturing glutathione (GSH), a typical intraCellular NPSH, in phosphate buffer. Among the three propargylic sulfones 1a – c , carboxylic acid derivative 1c showed the most potent radiosensitizing activity toward Hypoxic EMT6/KU tumor Cells. In view of these results and the partition coefficients between 1-octanol and water, we concluded that appropriate NPSH-depletion ability and lipophilicity are both important in achieving potent Hypoxic-Cell radiosensitization by propargylic sulfones possessing a 2-nitroimidazole function in biological systems.
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propargylic sulfones possessing a 2 nitroimidazole function novel Hypoxic Cell radiosensitizers with intraCellular non protein thiol depletion ability
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Kazuhito Tanabe, Ryusuke Kojima, Hiroshi Hatta, Seiichi NishimotoAbstract:Abstract Propargylic sulfones ( 1a – c ) containing a 2-nitroimidazole structure were synthesized, and their non-protein thiol (NPSH) depletion abilities were investigated. Propargylic sulfones 1a , c containing an electron withdrawing p -nitrophenyl group showed high reactivity toward capturing glutathione (GSH), a typical intraCellular NPSH, in phosphate buffer. Among the three propargylic sulfones 1a – c , carboxylic acid derivative 1c showed the most potent radiosensitizing activity toward Hypoxic EMT6/KU tumor Cells. In view of these results and the partition coefficients between 1-octanol and water, we concluded that appropriate NPSH-depletion ability and lipophilicity are both important in achieving potent Hypoxic-Cell radiosensitization by propargylic sulfones possessing a 2-nitroimidazole function in biological systems.
Kazuhito Tanabe - One of the best experts on this subject based on the ideXlab platform.
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propargylic sulfones possessing a 2 nitroimidazole function novel Hypoxic Cell radiosensitizers with intraCellular non protein thiol depletion ability
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Kazuhito Tanabe, Ryusuke Kojima, Hiroshi Hatta, Seiichi NishimotoAbstract:Abstract Propargylic sulfones ( 1a – c ) containing a 2-nitroimidazole structure were synthesized, and their non-protein thiol (NPSH) depletion abilities were investigated. Propargylic sulfones 1a , c containing an electron withdrawing p -nitrophenyl group showed high reactivity toward capturing glutathione (GSH), a typical intraCellular NPSH, in phosphate buffer. Among the three propargylic sulfones 1a – c , carboxylic acid derivative 1c showed the most potent radiosensitizing activity toward Hypoxic EMT6/KU tumor Cells. In view of these results and the partition coefficients between 1-octanol and water, we concluded that appropriate NPSH-depletion ability and lipophilicity are both important in achieving potent Hypoxic-Cell radiosensitization by propargylic sulfones possessing a 2-nitroimidazole function in biological systems.
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propargylic sulfones possessing a 2 nitroimidazole function novel Hypoxic Cell radiosensitizers with intraCellular non protein thiol depletion ability
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Kazuhito Tanabe, Ryusuke Kojima, Hiroshi Hatta, Seiichi NishimotoAbstract:Abstract Propargylic sulfones ( 1a – c ) containing a 2-nitroimidazole structure were synthesized, and their non-protein thiol (NPSH) depletion abilities were investigated. Propargylic sulfones 1a , c containing an electron withdrawing p -nitrophenyl group showed high reactivity toward capturing glutathione (GSH), a typical intraCellular NPSH, in phosphate buffer. Among the three propargylic sulfones 1a – c , carboxylic acid derivative 1c showed the most potent radiosensitizing activity toward Hypoxic EMT6/KU tumor Cells. In view of these results and the partition coefficients between 1-octanol and water, we concluded that appropriate NPSH-depletion ability and lipophilicity are both important in achieving potent Hypoxic-Cell radiosensitization by propargylic sulfones possessing a 2-nitroimidazole function in biological systems.
Andrew M Rauth - One of the best experts on this subject based on the ideXlab platform.
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isolation and characterization of a Cell line resistant to 5 3 2 nitro 1 imidazoyl propyl phenanthridinium bromide 2 nlp 3 a dna intercalating Hypoxic Cell radiosensitizer and cytotoxin
Biochemical Pharmacology, 1995Co-Authors: D S M Cowan, Robert A Mcclelland, Andrew M RauthAbstract:Abstract A DNA-targeted Hypoxic Cell radiosensitizer and cytotoxin, 5-[3-(2-nitro-1-imidazoyl)-propyl]-phenanthridinium bromide (2-NLP-3), has been shown previously to have increased efficacy over untargeted analogues in vitro . To further study the mechanism of action of this compound, a Cell line, CHO-1000, derived from Chinese hamster ovary (CHO) AA8-4 Cells was isolated. This Cell line is capable of continuously growing in a concentration of 2-NLP-3 approximately 10-fold greater than that tolerated by wild-type CHO Cells. The resistance of CHO-1000 to 2-NLP-3 was compared with that of the P-glycoprotein overexpressing, multidrug resistant Chinese hamster Cell line CH R -C5 (C5). The resistance of CHO-1000 Cells to the acute toxic effects of 2-NLP-3 under both Hypoxic and aerobic exposure conditions was intermediate to that of the sensitive CHO wild-type Cells and the resistant C5 Cells. A similar pattern was seen for the Hypoxic Cell radiosensitizing ability of 2-NLP-3. 2-NLP-3 produced significant depletion of glutathione under both Hypoxic and aerobic conditions in all three Cell lines studied, and the degree of depletion was correlated with drug toxicity. CHO-1000 and C5 Cells were significantly more resistant to colchicine and doxorubicin compared with wild-type Cells. The toxicity pattern of 2-NLP-3 and its comparison phenanthridinium ion, P3, was not the same for CHO-1000 Cells compared with C5 Cells. Verapamil was an effective agent for reversing the Hypoxic resistance to 2-NLP-3 in both CHO-1000 and C5 Cells, but only a partial reversal of aerobic resistance was observed in CHO-1000 Cells. These results indicate that the resistant phenotype of CHO-1000 is mediated to some degree by P-glycoprotein expression, but that other as yet unidentified factors are also involved.
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DNA-targeted 2-nitroimidazoles: in vitro and in vivo studies.
British journal of cancer, 1994Co-Authors: D S M Cowan, J. F. Matejovic, R. A. Mcclelland, Andrew M RauthAbstract:A series of compounds in which a 2-nitroimidazole is linked to a DNA intercalating phenanthridine moiety has been synthesised. Previously, three such compounds, termed nitroimidazole-linked phenanthridines or NLPs, were tested in vitro and showed a greatly enhanced molar efficiency as Hypoxic Cell radiosensitisers and cytotoxins compared with the untargeted 2-nitroimidazole, misonidazole. Since the cytoxicity of these compounds was shown to be inversely proportional to linker chain length while radiosensitising ability was dependent of it, compounds with five and six carbons in the chain were synthesised in an attempt to lower the toxicity of the drugs while increasing their ability to 'scan' DNA for target radicals. These compounds and a comparison series of n-alkylated phenathridinium ions have been characterised and evaluated in vitro using Chinese hamster ovary and V79 Cells and their effects compared with misonidazole. Based on in vitro results, one member of the series was selected and evaluated in vitro using a V79 spheroid tumour model and in vivo using an SCCVII transplantable tumour system. These studies have demonstrated the potential utility of this class of compound.
Paul Workman - One of the best experts on this subject based on the ideXlab platform.
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reduction of 3 amino l 2 4 benzotriazine l 4 di n oxide tirapazamine win 59075 sr 4233 to a dna damaging species a direct role for nadph cytochrome p450 oxidoreductase
Carcinogenesis, 1994Co-Authors: Sara A Fitzsimmons, Robert J Riley, Alexander D Lewis, Paul WorkmanAbstract:3-amino-1,2,4-benzotriazine-1,4-di-N-oxide (tirapazamine, WIN 59075, SR 4233, NSC 130181) has entered phase 1 clinical trials as a bioreductive Hypoxic Cell cytotoxin because of its novel structure and impressive selective cytotoxicity towards Hypoxic Cells. Understanding the enzymology and underlying mechanism of oxidative and reductive DNA damage may allow more optimal development and use of this agent and contribute to the rational design of new bioreductive drugs. Here we provide unambiguous evidence that WIN 59075 undergoes one-electron reduction by purified rat liver NADPH:cytochrome P450 oxidoreductase to generate single- and double-strand breaks in plasmid DNA. The DNA damage caused may be important for the therapeutic toxicity of the drug. Enzyme kinetic parameters for this oxidoreductase reaction are in the range 1.01-1.61 mM for Km and 4416-5099 nmol/min/mg for Vmax. The relative levels of expression and Cellular localization of target tumour NADPH:cytochrome P450 oxidoreductase may contribute to the therapeutic selectivity of WIN 59075.
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enzymology of the reduction of the potent benzotriazine di n oxide Hypoxic Cell cytotoxin sr 4233 win 59075 by nad p h quinone acceptor oxidoreductase ec 1 6 99 2 purified from walker 256 rat tumour Cells
Biochemical Pharmacology, 1992Co-Authors: Robert J Riley, Paul WorkmanAbstract:3-Amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233; WIN 59075) is a highly selective Hypoxic Cell cytotoxin soon to enter phase I clinical trial. The compound is thought to exert its action through a toxic one-electron reduced free radical intermediate. Preliminary data have suggested that SR 4233 may be metabolized by DT-diaphorase [NAD(P)H: (quinone acceptor) oxidoreductase (EC 1.6.99.2)] to both two- and four-electron reduced products and that this route of biotransformation may represent a bioprotection pathway. In this study, a highly purified enzyme preparation was employed in order to investigate further the metabolism of SR 4233 by DT-diaphorase and to examine the mechanism of reduction in more detail. Spectrophotometric analysis showed that SR 4233 underwent reduction by DT-diaphorase with an apparent Km of 1.23 +/- 0.27 mM and Vmax of 8.55 +/- 1.67 nmol/min/microgram protein. This reaction was inhibited completely by dicoumarol (100 microM) and partially by an antiserum raised against the purified enzyme. Characterization of the products of SR 4233 reduction by reverse-phase HPLC confirmed that both two- (SR 4317) and four- (SR 4330) electron reduction products were generated, the latter being the predominant metabolite, particularly in prolonged incubations. Further experiments showed that the four-electron reduction product, but not the two-electron reduction product, was also a substrate for DT-diaphorase with an apparent Km of 1.14 mM and a Vmax of 57.12 nmol/min/micrograms protein. The results presented confirm that SR 4233 is indeed a substrate for DT-diaphorase and that a mixture of two-, four- and six-electron reduced products may be formed. The possible toxicological and pharmacodynamic significance of this metabolism is discussed.