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

Publication ,  Journal Article
Schold, SC; Brent, TP; von Hofe, E; Friedman, HS; Mitra, S; Bigner, DD; Swenberg, JA; Kleihues, P
Published in: J Neurosurg
April 1989

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.

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Published In

J Neurosurg

DOI

ISSN

0022-3085

Publication Date

April 1989

Volume

70

Issue

4

Start / End Page

573 / 577

Location

United States

Related Subject Headings

  • Transplantation, Heterologous
  • Procarbazine
  • O(6)-Methylguanine-DNA Methyltransferase
  • Neurology & Neurosurgery
  • Neoplasm Transplantation
  • Mice, Nude
  • Mice
  • Methyltransferases
  • Medulloblastoma
  • Humans
 

Citation

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Schold, S. C., Brent, T. P., von Hofe, E., Friedman, H. S., Mitra, S., Bigner, D. D., … Kleihues, P. (1989). O6-alkylguanine-DNA alkyltransferase and sensitivity to procarbazine in human brain-tumor xenografts. J Neurosurg, 70(4), 573–577. https://doi.org/10.3171/jns.1989.70.4.0573
Schold, S. C., T. P. Brent, E. von Hofe, H. S. Friedman, S. Mitra, D. D. Bigner, J. A. Swenberg, and P. Kleihues. “O6-alkylguanine-DNA alkyltransferase and sensitivity to procarbazine in human brain-tumor xenografts.J Neurosurg 70, no. 4 (April 1989): 573–77. https://doi.org/10.3171/jns.1989.70.4.0573.
Schold SC, Brent TP, von Hofe E, Friedman HS, Mitra S, Bigner DD, et al. O6-alkylguanine-DNA alkyltransferase and sensitivity to procarbazine in human brain-tumor xenografts. J Neurosurg. 1989 Apr;70(4):573–7.
Schold, S. C., et al. “O6-alkylguanine-DNA alkyltransferase and sensitivity to procarbazine in human brain-tumor xenografts.J Neurosurg, vol. 70, no. 4, Apr. 1989, pp. 573–77. Pubmed, doi:10.3171/jns.1989.70.4.0573.
Schold SC, Brent TP, von Hofe E, Friedman HS, Mitra S, Bigner DD, Swenberg JA, Kleihues P. O6-alkylguanine-DNA alkyltransferase and sensitivity to procarbazine in human brain-tumor xenografts. J Neurosurg. 1989 Apr;70(4):573–577.

Published In

J Neurosurg

DOI

ISSN

0022-3085

Publication Date

April 1989

Volume

70

Issue

4

Start / End Page

573 / 577

Location

United States

Related Subject Headings

  • Transplantation, Heterologous
  • Procarbazine
  • O(6)-Methylguanine-DNA Methyltransferase
  • Neurology & Neurosurgery
  • Neoplasm Transplantation
  • Mice, Nude
  • Mice
  • Methyltransferases
  • Medulloblastoma
  • Humans