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Int J Med Sci 2009; 6(6):338-347. doi:10.7150/ijms.6.338

Research Paper

High-Resolution Flow Cytometry: a Suitable Tool for Monitoring Aneuploid Prostate Cancer Cells after TMZ and TMZ-BioShuttle Treatment

Klaus Braun1 # ✉, Volker Ehemann2 #, Manfred Wiessler1, Ruediger Pipkorn3, Bernd Didinger4, Gabriele Mueller5, Waldemar Waldeck5

1. German Cancer Research Center, Dept. of Medical Physics in Radiooncology, INF 280, D-69120 Heidelberg, Germany
2. University of Heidelberg, Institute of Pathology, INF 220, D-69120 Heidelberg, Germany
3. German Cancer Research Center, Central Peptide Synthesis Unit, INF 580, D-69120 Heidelberg, Germany
4. Radiation Oncology, University of Heidelberg, INF 400, D-69120 Heidelberg, Germany
5. German Cancer Research Center, Division of Biophysics of Macromolecules, INF 580, D-69120 Heidelberg, Germany
# The authors contributed by equal parts to this work

Abstract

If metastatic prostate cancer gets resistant to antiandrogen therapy, there are few treatment options, because prostate cancer is not very sensitive to cytostatic agents. Temozolomide (TMZ) as an orally applicable chemotherapeutic substance has been proven to be effective and well tolerated with occasional moderate toxicity especially for brain tumors and an application to prostate cancer cells seemed to be promising. Unfortunately, TMZ was inefficient in the treatment of symptomatic progressive hormone-refractory prostate cancer (HRPC). The reasons could be a low sensitivity against TMZ the short plasma half-life of TMZ, non-adapted application regimens and additionally, the aneuploid DNA content of prostate cancer cells suggesting different sensitivity against therapeutical interventions e.g. radiation therapy or chemotherapy. Considerations to improve this unsatisfying situation resulted in the realization of higher local TMZ concentrations, sufficient to kill cells regardless of intrinsic cellular sensitivity and cell DNA-index. Therefore, we reformulated the TMZ by ligation to a peptide-based carrier system called TMZ-BioShuttle for intervention. The modular-composed carrier consists of a transmembrane transporter (CPP), connected to a nuclear localization sequence (NLS) cleavably-bound, which in turn was coupled with TMZ. The NLS-sequence allows an active delivery of the TMZ into the cell nucleus after transmembrane passage of the TMZ-BioShuttle and intra-cytoplasm enzymatic cleavage and separation from the CPP. This TMZ-BioShuttle could contribute to improve therapeutic options exemplified by the hormone refractory prostate cancer. The next step was to syllogize a qualified method monitoring cell toxic effects in a high sensitivity under consideration of the ploidy status. The high-resolution flow cytometric analysis showed to be an appropriate system for a better detection and distinction of several cell populations dependent on their different DNA-indices as well as changes in proliferation of cell populations after chemotherapeutical treatment.

Keywords: TMZ-BioShuttle, Prostate Cancer Cells, Flow Cytometry

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How to cite this article:
Braun K, Ehemann V, Wiessler M, Pipkorn R, Didinger B, Mueller G, Waldeck W. High-Resolution Flow Cytometry: a Suitable Tool for Monitoring Aneuploid Prostate Cancer Cells after TMZ and TMZ-BioShuttle Treatment. Int J Med Sci 2009; 6(6):338-347. doi:10.7150/ijms.6.338. Available from http://www.medsci.org/v06p0338.htm