The Response of Human Cells to In Vivo Methylation Damage

  • B. Strauss
  • D. Sagher
  • T. Karrison
  • R. Larson
  • P. Meier
  • J. Schwartz
  • R. Farber
  • R. Weichselbaum
Chapter

Summary

Individuals with Hodgkin’s disease (HD) may be treated by a chemotherapeutic regimen which includes procarbazine, a compound metabolized to a methylating species. A small group of all HD patients eventually develop acute nonlymphocytic leukemia (ANLL) some years after therapy (t-ANLL). We therefore initiated a study of the O6− methylguanine DNA methyltransferase (MT) activity in normal controls and in patients with HD, ANLL de novo or t-ANLL. As part of the study we also prepared lymphoblastoid lines by Epstein Barr virus (EBV) transformation of peripheral blood lymphocytes (PBL’s). We express MT activity per gg of DNA. The activity in normal individuals varies from about 2.2 to 14.7 fmol/µg of DNA with a mean ± SE of 7.2 ± 0.35. HD patients before treatment have MT values of 5.6 ± 0.53. The MT value of HD patients receiving procarbazine was 4.3 ± 0.52; t-ANLL patients before treatment gave 4.2 ± 0.63; six recently diagnosed ANLL patients had MT values of 7.8 ± 1.72, and 13 ANLL patients in remission had MT activities of 9.3 ± 2.3. The differences in MT value between normal subjects and HD patients, between t-ANLL and normal subjects, and between ANLL de novo and t-ANLL groups are significant. There is significant variation in the MT values of normal PBL’s sampled at different times. MT activity diminishes slightly with age in both normal and HD groups, but this does not account for the observed differences between normal and HD groups. We find a significant correlation between the MT activity of PBL’s and of the lines derived from them, particularly when normal or untreated individuals are used as the source of the lines. There is variation in the the MT values of successive lines from the same individual, but it is within a factor of about two in these experiments. Although there is significant variation in repeated samples of PBL’s from the same individual, patients with Hodgkin’s disease have significantly lower MT activity than do normal controls. In addition, the HD group includes individuals with almost no MT activity. The observation that individuals with t-ANLL have lower MT activity than either controls or ANLL patients de novo and that HD patients on procarbazine have reduced levels as compared to HD patients before treatment would, if confirmed, lend credence to the hypothesis that MT levels play a role in the etiology of secondary malignancy. There is a clear relationship between the MT level in lymphocytes and in the lines derived from them. We interpret these results to mean that the MT level of a cell is a characteristic which survives the events of EBV transformation.

Keywords

Epstein Barr Virus Sister Chromatid Exchange Acute Nonlymphocytic Leukemia Immune Deficiency Disease Lymphoblastoid Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 1989

Authors and Affiliations

  • B. Strauss
    • 1
  • D. Sagher
    • 1
  • T. Karrison
    • 1
  • R. Larson
    • 1
  • P. Meier
    • 1
  • J. Schwartz
    • 1
  • R. Farber
    • 1
  • R. Weichselbaum
    • 1
  1. 1.The University of Chicago Cancer Research Center and the Departments of Molecular Genetics and Cell Biology, Pharmacological and Physiological Sciences, Medicine, Statistics and Radiation OncologyThe University of ChicagoChicagoUSA

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