Ganciclovir uptake in human mammary carcinoma cells expressing herpes simplex virus thymidine kinase

Uwe Haberkorn, Khashayarsha Khazaie, Iris Morr, Annette Altmann, Markus Müller, Gerhard Van Kaick

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Assessment of suicide enzyme activity would have considerable impact on the planning and the individualization of suicide gene therapy of malignant tumors. This may be done by determining the pharmacokinetics of specific substrates. We generated ganciclovir (GCV)-sensitive human mammary carcinoma cell lines after transfection with a retroviral vector bearing the herpes simplex virus thymidine kinase (HSV-tk) gene. Thereafter, uptake measurements and HPLC analyses were performed up to 48 h in an HSV-tk-expressing cell line and in a wild-type cell line using tritiated GCV. HSV-tk-expressing cells showed higher GCV uptake and phosphorylation than control cells, whereas in wild-type MCF7 cells no phosphorylated GCV was detected. In bystander experiments the total GCV uptake was related to the amount of HSV-tk- expressing cells. Furthermore, the uptake of GCV correlated closely with the growth inhibition (r = 0.92). Therefore, the accumulation of specific substrates may serve as an indicator of the HSV-tk activity and of therapy outcome. Inhibition and competition experiments demonstrated slow transport of GCV by the nucleoside carriers. The slow uptake and low affinity to HSV- tk indicate that GCV is not an ideal substrate for the nucleoside transport systems or for HSV-tk. This may be the limiting factor for therapy success, necessitating the search for better substrates of HSV-tk.

Original languageEnglish (US)
Pages (from-to)367-373
Number of pages7
JournalNuclear Medicine and Biology
Volume25
Issue number4
DOIs
StatePublished - May 1 1998

Keywords

  • Ganciclovir
  • Gene therapy
  • HSV thymidine kinase
  • Mammary carcinoma

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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