p53 mutations, O6‐alkylguanine DNA alkyltransferase activity, and sensitivity to procarbazine in human brain tumors

Background. In human brain tumors, sensitivity to procarbazine as measured by sensitivity in a xenograft tumor model correlated inversely with amounts of the DNA repair enzyme O6‐alkylguanine DNA alkyltransferase(AT). Methods. To test the hypothesis that mutations of the p53 tumor suppressor gene in...

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Bibliographic Details
Published in:Cancer 1995-03, Vol.75 (6), p.1339-1342
Main Authors: Russell, Susan J., Ye, Yun‐Wei, Waber, Pamela G., Shuford, Matthew, Schold, S. Clifford, Nisen, Perry D.
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Base Sequence
Biological and medical sciences
Brain Neoplasms - drug therapy
Brain Neoplasms - enzymology
Brain Neoplasms - genetics
Brain Neoplasms - pathology
Cell Cycle
DNA Mutational Analysis
DNA Repair
General aspects
Genes, p53 - genetics
glioblastoma
Humans
Medical sciences
medulloblastoma
Methyltransferases - metabolism
Mice
Mice, Nude
Molecular Sequence Data
Mutation
Neoplasm Transplantation
O-Methylguanine-DNA Methyltransferase
O6‐alkylguanine DNA alkyltransferase
p53
Pharmacology. Drug treatments
Polymerase Chain Reaction
Procarbazine - therapeutic use
Tumor Cells, Cultured
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Summary:Background. In human brain tumors, sensitivity to procarbazine as measured by sensitivity in a xenograft tumor model correlated inversely with amounts of the DNA repair enzyme O6‐alkylguanine DNA alkyltransferase(AT). Methods. To test the hypothesis that mutations of the p53 tumor suppressor gene in human tumors also can correlate with the response to chemotherapy, p53 mutations were identified in primary human malignant brain tumors and cell lines in which AT activity and procarbazine sensitivity in a xenograft model was ascertained. Results. Mutations were identified in 7 of 21 (33%) specimens tested. Specimens containing p53 mutations tended to exhibit an increased growth delay in procarbazine‐treated xenografts and lower amounts of AT. Conclusions. p53 mutations in brain tumors may contribute to procarbazine sensitivity by failing to induce arrest at the G1/S cell‐cycle checkpoint, thereby preventing the repair of procarbazine‐induced genetic alterations. Cancer 1995;75:1339‐42.
ISSN:0008-543X
1097-0142
DOI:10.1002/1097-0142(19950315)75:6<1339::AID-CNCR2820750616>3.0.CO;2-F