Decreased DNA topoisomerase II alpha expression and cold-sensitive growth in a mouse mammary cancer cell line resistant to etoposide and doxorubicin

Oncol Res. 1996;8(5):197-206.


A mouse mammary carcinoma FM3A cell line resistant to the DNA topoisomerase (topo) II-targeting agent, etoposide (VP-16), FM3A/VP-2B, had a markedly reduced growth rate at a low temperature (33 degrees C). The cells had the following properties: (a) FM3A/VP-2B, which had 24-fold higher resistance to VP-16 than its parental line, FM3A, was cross-resistant to doxorubicin, but not to a camptothecin derivative, CPT-11. (b) Cold-resistant revertants from FM3A/VP-2B, R-6 and R-11, remained 8- to 9-fold more resistant to VP-16 and 2- to 3-fold more resistant to doxorubicin. (c) FM3A/VP-2B had one-fourth the level of topo II activity and one-third of the topo II alpha content and mRNA of FM3A. R-6 and R-11, however, had levels similar to FM3A. (d) FM3A/VP-2B and FM3A had a 3-base deletion at position 4170 on one allele on the topo II alpha cDNA, but expression of the wild-type and the deletion allele was not appreciably changed in both cell lines. Decreased topo II alpha expression might have led to the acquisition of drug resistance to etoposide in FM3A/VP-2B, and appeared to be linked with the cold-sensitive growth. We also present a corrected mouse topo II alpha cDNA sequence.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibiotics, Antineoplastic / pharmacology*
  • Antigens, Neoplasm / metabolism*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Blotting, Northern
  • Cell Division / drug effects
  • Cold Temperature
  • DNA Topoisomerases, Type I / metabolism
  • DNA Topoisomerases, Type II* / chemistry
  • DNA Topoisomerases, Type II* / metabolism*
  • DNA-Binding Proteins
  • Doxorubicin / pharmacology*
  • Drug Resistance
  • Etoposide / pharmacology*
  • Female
  • Isoenzymes / chemistry
  • Isoenzymes / metabolism*
  • Mammary Neoplasms, Experimental / enzymology*
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Molecular Sequence Data
  • Phenotype
  • Tumor Cells, Cultured


  • Antibiotics, Antineoplastic
  • Antigens, Neoplasm
  • Antineoplastic Agents, Phytogenic
  • DNA-Binding Proteins
  • Isoenzymes
  • Etoposide
  • Doxorubicin
  • DNA Topoisomerases, Type I
  • DNA Topoisomerases, Type II