Effect of thiols exported by cancer cells on the stability and growth-inhibitory activity of Pt(IV) complexes

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• 作者：Nicole A. Kratochwil and Patrick J. Bednarski
• 关键词：Key words Thiol release ; Pt(IV) complexes ; Stability ; Cancer cell lines ; Metabolism
• 刊名：Journal of Cancer Research and Clinical Oncology
• 出版年：1999
• 出版时间：November 1999
• 年：1999
• 卷：125
• 期：12
• 页码：690-696
• 全文大小：129 KB
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Oncology
  Cancer Research
  Internal Medicine
  Hematology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1335

文摘

Purpose: The role of thiols in the reduction of Pt(IV) antitumor agents to Pt(II) is well recognized and it is widely thought that this reaction is required for activity. The sources of extracellular thiols in cell culture have been less studied. The purpose of the present work was to determine whether the stability of Pt(IV) complexes in culture medium can be affected by thiols that are released by cancer cells. Methods: A two-column HPLC assay with UV/visible detection was used to determine the stability of two Pt(IV) complexes in culture medium with and without cells. The kinetics of the thiol release from a human ovarian cancer cell line SK-OV-3 and a human glioblastoma cell line U-87 MG were determined by a modification of the Ellman's method. Results: The stability of a Pt(IV) complex with equatorial iodo ligands, trans,cis-[Pt(en)(OAc)₂I₂], was dramatically lower in culture medium in the presence of cells than in fresh culture medium, whereas the half-life of the dichloro analog, trans,cis-[Pt(en)(OAc)₂Cl₂], was somewhat increased. Although both complexes showed similar in vitro cell-growth-inhibitory activity, trans, cis-[Pt(en)(OAc)₂Cl₂] required a longer incubation time than the iodo analog to reach its maximal effect. The thiol content of the culture medium in the presence of cells was measured after 2 days: the concentrations from cultures of U-87 MG and SK-OV-3 cells were 3.6?± 0.1?μM and 9.3?±?0.1?μM respectively, compared to 0.07?±?0.04?μM in fresh medium. During the rapid growth phase, the extracellular thiol content reached a maximum of 20.0?±?0.5?μM and 47.8?±?0.2?μM for U-87?MG and SK-OV-3 cells respectively. Conclusions: These findings show that the culture medium conditioned by cancer cells can influence the stabilities of certain Pt(IV) complexes in cytotoxicity studies.