Effects of an inducible anti-sense c-myc gene transfer in a drug-resistant human small-cell-lung-carcinoma cell line.

Academic Article

Abstract

  • Small-cell-lung-cancer (SCLC) is characterized by rapid development of resistance to cytotoxic agents, such as cisplatin (cDDP) and anthracyclines. c-myc over-expression is one of the reported genetic alterations in this tumor. Amplification of the c-myc gene in this and other cancers is often correlated with poor prognosis. We studied the existence of a correlation between resistance and activation of the c-myc oncogene in a cDDP-resistant SCLC sub-line, GLC4cDDP, containing a c-myc gene amplification. This cell line was stably transfected with either an anti-sense c-myc (AS) or control (C) expression vector resulting in the sub-clones GLC4cDDP/AS and GLC4cDDP/C respectively. PCR and RT-PCR analysis illustrated the integration and activation of the dexamethasone(dex)-inducible MMTV-LTR promoter linked to the complete AS-c-myc fragment in GLC4cDDP/AS cells, but not in GLC4cDDP/C cells. Dex-induced AS-c-myc RNA resulted in 50% growth inhibition during the first 48 hr, which declined to 25% at 72 hr. In addition, AS-c-myc RNA expression reduced the cloning efficacy by 36% and induced 2-fold more apoptosis within 24 hr in GLC4cDDP/AS cells. Dex treatment did not affect the proliferation, clonogenicity and induction of apoptosis in the control cell lines. Furthermore, AS-c-myc RNA expression caused a 1.4-fold increased cDDP sensitivity but no change in doxorubicin or vincristine sensitivity in GLC4cDDP/AS cells. Our results indicate that AS-c-myc RNA expression causes inhibition of cell proliferation, induces apoptosis, reduces clonogenicity and interferes with cDDP sensitivity but not with doxorubicin or vincristine sensitivity.
  • Keywords

  • Carcinoma, Small Cell, Cell Cycle, Cell Division, Drug Resistance, Neoplasm, Gene Transfer Techniques, Genes, myc, Genetic Vectors, Genotype, Humans, Lung Neoplasms, Polymerase Chain Reaction, RNA, Antisense, Transfection, Tumor Cells, Cultured
  • Author List

  • Van Waardenburg RC; Meijer C; Burger H; Nooter K; De Vries EG; Mulder NH; De Jong S
  • Start Page

  • 544
  • End Page

  • 550
  • Volume

  • 73
  • Issue

  • 4