O6-Alkylguanine-DNA alkyltransferase and sensitivity to procarbazine in human brain-tumor xenografts

S. C. Schold, T. P. Brent, E. Von Hofe, H. S. Friedman, S. Mitra, D. D. Bigner, J. A. Swenberg, P. Kleihues

Research output: Contribution to journalArticle

138 Scopus citations

Abstract

The level of O6-alkylguanine-deoxyribonucleic acid (DNA) alkyltransferase (AT) was determined in 15 human brain-tumor xenografts in athymic mice. This enzyme is a primary intracellular repair mechanism for lesions produced at the O6 position of guanine by a wide range of alkylating agents, including nitrosoureas and procarbazine. Its activity ranged from undetectable in five tumor lines to 2338 fmol/mg protein in N-1941, a human glioblastoma xenograft. The sensitivity of 10 of these xenografts to procarbazine was determined and it was found that four of the five tumor lines with AT levels of more than 100 fmol/mg protein had growth delays after procarbazine treatment of less than 20 days, whereas all five lines with undetectable AT levels had growth delays of over 30 days. The primary cytotoxic DNA adduct produced by procarbazine (namely, O6-methylguanine) was found to be significantly higher in two sensitive lines with low AT levels than in a highly resistant line with a high AT level. These data suggest that the AT levels of individual brain tumors can be used as predictive indicators of their susceptibility to drugs that exert their antineoplastic effect primarily by O6-alkylation of guanine in nuclear DNA.

Original languageEnglish (US)
Pages (from-to)573-577
Number of pages5
JournalJournal of Neurosurgery
Volume70
Issue number4
DOIs
StatePublished - 1989

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

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