Mutation of p53 and consecutive selective drug resistance in B-CLL occurs as a consequence of prior DNA-damaging chemotherapy.
Cell Death Differ
; 10(4): 477-84, 2003 Apr.
Article
in En
| MEDLINE
| ID: mdl-12719725
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Vidarabine
/
DNA Damage
/
Leukemia, Lymphocytic, Chronic, B-Cell
/
Tumor Suppressor Protein p53
/
Drug Resistance, Neoplasm
/
Antineoplastic Agents, Alkylating
/
Mutation
Type of study:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Cell Death Differ
Year:
2003
Type:
Article
Affiliation country:
Germany