Abstract
Knowledge of the type of biological reaction to chemotherapy is a prerequisite for its rational enhancement. We previously showed that irinotecan-induced DNA damage triggers in the HCT116p53wt colon carcinoma cell line a long-term cell cycle arrest and in HCT116p53−/− cells apoptosis (Magrini et al., 2002). To compare the contribution of long-term cell cycle arrest and that of apoptosis to inhibition of cell proliferation after irinotecan-induced DNA damage, we used this isogenic system as well as the cell lines LS174T (p53wt) and HT-29 (p53mut). Both p53wt cell lines responded to damage by undergoing a long-term tetraploid G1 arrest, whereas the p53mut cell lines underwent apoptosis. Cell cycle arrest as well as apoptosis caused a similar delay in cell proliferation. Irinotecan treatment also induced in mouse tumours derived from the p53wt cell lines a tetraploid G1 arrest and in those derived from the p53-deficient cell lines a transient G2/M arrest and apoptosis. The delay of tumour growth was in the same range in both groups, that is, arrest- and apoptosis-mediated tumour growth inhibition was comparable. In conclusion, cell cycle arrest as well as apoptosis may be equipotent mechanisms mediating the chemotherapeutic effects of irinotecan.
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Abbreviations
- p53wt:
-
p53 wild type
- p53mut:
-
p53 mutated
- CPT-11:
-
irinotecan
- SN-38:
-
irinotecan metabolite 7-ethyl-10-hydroxycamptothecin
- ASPP:
-
apoptosis stimulating protein of p53
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Acknowledgements
We acknowledge the perfect technical assistance provided by Britta Jebautzke and the contribution of Brita Vorwerk to Figure 6. This work was supported by the Sonnenfeld Stiftung and Monika Kutzner Stiftung. SN-38 was a kind gift from Agnes Gonthier, Aventis Pharma S.A., Vitry-sur-Seine, Cedex France.
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Bhonde, M., Hanski, ML., Notter, M. et al. Equivalent effect of DNA damage-induced apoptotic cell death or long-term cell cycle arrest on colon carcinoma cell proliferation and tumour growth. Oncogene 25, 165–175 (2006). https://doi.org/10.1038/sj.onc.1209017
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DOI: https://doi.org/10.1038/sj.onc.1209017
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