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 human tumors also can correlate with the response to chemotherapy, p53 mutations2 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.
Russell
S J
SJ
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235-9063.
Ye
Y W
YW
Waber
P G
PG
Shuford
M
M
Schold
S C
SC
Nisen
P D
PD
D000818:Animals; D001483:Base Sequence; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle; D004252:DNA Mutational Analysis; D004260:DNA Repair; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009154:Mutation; D009368:Neoplasm Transplantation; D019853:O(6)-Methylguanine-DNA Methyltransferase; D016133:Polymerase Chain Reaction; D011344:Procarbazine / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D011344:Procarbazine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase