Development of a syngenic brain-tumor model resistant to chloroethyl-nitrosourea using a methylguanine DNA methyltransferase cDNA

Anticancer Res. Nov-Dec 1999;19(6B):5313-8.

Abstract

Chloroethyl-nitrosourea (CENU) is one of the most potent chemotherapeutic agents for brain tumors. However, acquired resistance to this drug has become a serious problem in the treatment of brain tumor patients. The main mechanism of the resistance is a recruitment of the O6-methylguanine-DNA- methyltransferase (MGMT) in tumor cells. Many approaches, including treatment with enzyme-depletions, antibodies, antisenses, and a ribozyme, have been reported to successfully overcome the resistance. In order to evaluate these approaches properly, we designed a syngenic rat brain-tumor model resistant to CENU. The 9L rat gliosarcoma cells were retrovirally transduced with MGMT cDNA and stereotactically implanted into the brain parenchyma. In this model, rats inoculated with resistant cells died significantly earlier than did rats with control cells after treatment with CENU. Because of the limited intracranial space, the animals presented a restricted survival. Since the survival was sensitive and reproducible, this system may have a role in the evaluation of approaches to drug-resistant brain-tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics
  • DNA, Complementary
  • Disease Models, Animal
  • Drug Resistance, Neoplasm
  • Ethylnitrosourea / analogs & derivatives*
  • Ethylnitrosourea / therapeutic use
  • Gliosarcoma / drug therapy*
  • Gliosarcoma / genetics
  • Male
  • O(6)-Methylguanine-DNA Methyltransferase / genetics*
  • Rats
  • Rats, Inbred F344
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • DNA, Complementary
  • 1-(2-chloroethyl)-1-nitrosourea
  • O(6)-Methylguanine-DNA Methyltransferase
  • Ethylnitrosourea