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KMID : 0369820060360040231
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Jorunal of Korean Pharmaceutical Sciences
2006 Volume.36 No. 4 p.231 ~ p.237
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Pharmacodynamics of Tirapazamine in Histocultures of a Human Lung Adenocarcinoma Xenograft
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박종국/Park JK
구효정/Kuh HJ
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Abstract
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Hypoxia in solid tumors is known to contribute to intrinsic chemoresistance. Histocultures are in vitro 3 dimensional cultures of tumor tissues and maintain the characteristic microenvironment of human solid tumors in vivo including hypoxia and multicellular structure. In this study, we evaluated the pharmacodynamics of tirapazamine(TPZ), a hypoxia-selective cytotoxin, in human non small cell lung cancer(NSCLC) cells grown as monolayers and histocultures. Antiproliferative activity of TPZ was determined after various conditions of drug exposure, and cell cycle arrest and apoptosis were also measured using flow cytometry. In monolayers, hypoxia selectivity measured by hypoxic/normoxic cytotoxicity ratio was increased with longer exposure. Lower cytotoxicity of TPZ was observed in histocultures compared to monolayers, however, a similar level of cytotoxicity was obtained with longer exposure of 96 hr. TPZ induced G2/M arrest and apoptosis in both culture conditions, which were greatly enhanced under hypoxic condition. Our data clearly showed the different pharmacodynamics of TPZ in monolayers and histocultures. Antiproliferative activity of TPZ against human solid tumors can be improved with longer drug exposure by exploiting drug delivery systems or by combining angiogenesis inhibitors to maintain drug concentration in tumor tissues.
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KEYWORD
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Tirapazamine, Histocultures, Cell cycle, Apoptosis, Pharmacodynamics
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