Wild-type p53 renders mouse astrocytes resistant to 1,3-Bis(2-chloroethyl)-1-nitrosourea despite the absence of a p53-dependent cell cycle arrest [corrected].
We examined the response of normal and p53-deficient mouse astrocytes to the alkylating agent 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU), a clinically useful DNA-damaging drug to which some human astrocytomas are resistant and some are sensitive. Astrocyte cultures were isolated from the cerebrums of wild-type, heterozygous, and knockout p53 neonatal mice and treated with various concentrations of BCNU. Wild-type p53 astrocytes were significantly more resistant to BCNU than were knockout p53 astrocytes, with heterozygous astrocytes exhibiting an intermediate level of resistance, Cell cycle analysis showed that wild-type p53 astrocytes treated with BCNU demonstrated a decline in the percentage of cells in G1 and an increase in the percentage of cells in G2. Similar cell cycle responses to BCNU occurred in knockout p53 astrocytes, suggesting that this effect was p53 independent. In contrast, G1 arrest was observed in wild-type astrocytes exposed to ionizing radiation and was not observed in knockout astrocytes, indicating a p53-dependent response. Our findings point to an as yet uncharacterized p53-associated mechanism of resistance to BCNU in mouse astrocytes.
Nutt
C L
CL
Department of Oncology, University of Western Ontario, London, Ontario, Canada.
Chambers
A F
AF
Cairncross
J G
JG
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000528:radiation effects; D002330:Carmustine / Q000494:pharmacology*; D002460:Cell Line; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D016193:G1 Phase / Q000528:radiation effects; D016195:G2 Phase / Q000187:drug effects*; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D018906:Antineoplastic Agents, Alkylating; D016159:Tumor Suppressor Protein p53; D002330:Carmustine