Effects of an inducible anti-sense c-myc gene transfer in a drug-resistant human small-cell-lung-carcinoma cell line.
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.
Van Waardenburg
R C
RC
Division of Medical Oncology, University Hospital Groningen, The Netherlands.
Meijer
C
C
Burger
H
H
Nooter
K
K
De Vries
E G
EG
Mulder
N H
NH
De Jong
S
S
D018288:Carcinoma, Small Cell / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle; D002455:Cell Division; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D018014:Gene Transfer Techniques; D016259:Genes, myc / Q000235:genetics*; D005822:Genetic Vectors / Q000235:genetics; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D016372:RNA, Antisense / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured
D016372:RNA, Antisense