Mutation of p53 and consecutive selective drug resistance in B-CLL occurs as a consequence of prior DNA-damaging chemotherapy

Item Type:	Article
Title:	Mutation of p53 and consecutive selective drug resistance in B-CLL occurs as a consequence of prior DNA-damaging chemotherapy
Creators Name:	Sturm, I. and Bosanquet, A.G. and Hermann, S. and Guener, D. and Doerken, B. and Daniel, P.T.
Abstract:	Inactivation of p53 has been shown to correlate with poor prognosis and drug resistance in malignant tumors. Nevertheless, few reports have directly shown such effects in primary tumor cells. Here, we investigated the p53 mutational status in 138 B-CLL samples and compared these findings with drug and {gamma}-irradiation sensitivity profiles. p53 mutations resulted not only in a shorter survival but, notably also in selective resistance to alkylating agents, fludarabine and {gamma}-irradiation. In contrast, no such effect was observed for vincristine, anthracyclines and glucocorticoids. Thus, these latter compounds induce cell death at least in part by p53-independent pathways. Interestingly, p53 mutations clustered in patients who had received prior chemotherapy. In fact, we show for the first time that treatment with DNA-damaging alkylating agents correlates with occurrence of p53 mutations in a clinical setting. This finding may explain at least to some extent the development of resistance to second-line anticancer chemotherapy.
Keywords:	p53 mutation, Alkylating drugs, Apoptosis, Drug sensitivity, B-CLL
Source:	Cell Death and Differentiation
ISSN:	1350-9047
Publisher:	Nature Publishing Group
Volume:	10
Number:	4
Page Range:	477-484
Date:	1 April 2003
Official Publication:	https://doi.org/10.1038/sj.cdd.4401194
PubMed:	View item in PubMed

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