Journal of Pharmaceutical Investigation

The Korean Society of Pharmaceutical Sciences and Technology (한국약제학회)
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Pharmacodynamics of Tirapazamine in Histocultures of a Human Lung Adenocarcinoma Xenograft

인체폐암세포 조직배양계(histocultures)에서 티라파자민의 약력학

  • Park, Jong-Kook (Dept. of Biomedical Sciences, College of Medicine, The Catholic Univ. of Korea) ;
  • Kuh, Hyo-Jeong (Dept. of Biomedical Sciences, College of Medicine, The Catholic Univ. of Korea)
  • 박종국 (가톨릭대학교 의과대학 생명의과학과) ;
  • 구효정 (가톨릭대학교 의과대학 생명의과학과)
  • Published : 2006.08.21
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Abstract

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 $G_2/M$ 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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