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Radiochemotherapy with paclitaxel: Synchronization effects and the role of p53

Radiochemotherapie mit Paclitaxel: Synchronisationseffekte und die Rolle von p53

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Abstract

Purpose

We have studied the interaction of paclitaxel (Taxol) and radiation in V79 cells and human lymphoblasts with special emphasis on cell cycle effects and the role of p53.

Material and Methods

V79 cells in log- and plateau-phase and human lymphoblasts (p53wt TK6 and p53mut WTK1) were used. Paclitaxel was given for 2 hours. Survival was determined using clonogenic assays. Cell cycle analysis was done using DNA flow cytometry.

Results

In V79 cells there was a dose dependent delay of colony formation after paclitaxel. The LD50 was about 0.4 μM with a 2-hour exposure. In exponentially growing cells, there was an accumulation of 40% of cells in G2/M 6 hours after paclitaxel. The dose modification factor was about 3.9 when radiation was given 6 hours after 0.3 μM paclitaxel for 2 hours. Synchronization experiments using serum starvation and induction showed that synchronization was not sufficient to induce a comparable dose modification factor. Human lymphoblasts with mutated p53 (WTK1, LD50=75 μM) were more resistant to paclitaxel than wild type p53 cells (TK6, LD50=25 μM).

Conclusion

The radiosensitization induced by paclitaxel was critically dependent on the timing of irradiation and chemotherapy, although synchronization alone was not sufficient to explain the dose modification. Lymphoblasts with mutated p53 were less sensitive than wild type p53 cells.

Zusammenfassung

Ziel

Wir untersuchten die Interaktion von Paclitaxel (Taxol) und Bestrahlung in V79-Zellen und human en Lymphoblasten unter besonderer Berticksichtigung der Zellzykluseffekte und der Rolle von p53.

Material und Methodik

V79-Zellen in Exponential- und Plateauphase und humane Lymphoblasten (p53wt TK6 und p53mut WTK1) wurden benutzt. Paclitaxel wurde jeweils für zwei Stunden gegeben. Das zelluläre Überleben wurde mit klonogenen Assays bestimmt. Die Zellzyklusanalysen wurden mit der DNA-Flußzytometrie durchgeführt.

Ergebnisse

Bei V79-Zellen wurde eine dosisabhängige Verzögerung der Koloniebildung beobachtet. Die LD50 lag nach einer Zwei-Stunden-Exposition bei 0,4 μM. Bei exponentiell wachsenden Zellen kam es zu einer Akkumulation von 40% der Zellen in der G2/M-Phase sechs Stunden nach Paclitaxel-Gabe. Der Dosismodifikationsfaktor lag bei 3,9, wenn sechs Stunden nach Applikation von 0,3 μM Paclitaxel bestrahlt wurde. Die Synchronisationsexperimente mit Serumentzug und -induktion zeigten, daß die Synchronisation allein nicht ausreichte, einen vergleichbaren Effekt zu erzielen. Die humanen Lymphoblasten mit mutiertem p53 (WTK1, LD50=75 μM) waren resistenter für Paclitaxel als die p53-Wildtypzellen (TK6, LD50=25 μM).

Schlußfolgerung

Die Radiosensibilisierung durch Paclitaxel hängt ganz wesentlich von der zeitlichen Abfolge der Bestrahlung und der Chemotherapie ab, obwohl die Synchronisation allein nicht ausreicht, urn den Dosismodifikationsfaktor zu erklären, Lymphoblasten mit mutiertem p53 waren weniger empfindlich als p53-Wildtypzellen.

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Authors and Affiliations

  1. Laboratory for Molecular and Cellular Radiobiology (Chairman: Prof. Dr. Dr. M. Wannenmacher), Department of Clinical Radiology, University of Heidelberg, Heidelberg

    Klaus J. Weber

  2. Radiologische Universitätsklinik, Im Neuenheimer Feld 400, D-69120, Heidelberg, Germany

    Frederik Wenz

Authors
  1. Frederik Wenz
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  2. Stefan Greiner
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  3. Florence Germa
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  4. Karin Mayer
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  5. Detlev Latz
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  6. Klaus J. Weber
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Corresponding author

Correspondence to Frederik Wenz.

Additional information

Paclitaxel was provided by Bristol-Arzneimittel, München/Germany. Human lymphoblasts were a kind gift from Prof. J. B. Little, Harvard School of Public Health, Boston/MA.

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Wenz, F., Greiner, S., Germa, F. et al. Radiochemotherapy with paclitaxel: Synchronization effects and the role of p53. Strahlentherapie und Onkologie 175 (Suppl 3), 2–6 (1999). https://doi.org/10.1007/BF03215919

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  • DOI: https://doi.org/10.1007/BF03215919

Key Words

Schlusselworten Paclitaxel

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