c-myc antisense oligodeoxyribonucleotides inhibit proliferation of non-small cell lung cancer

Lary A. Robinson, Larry J. Smith, Michele P. Fontaine, H. David Kay, Charles P. Mountjoy, Samuel Jay Pirruccello

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Background.: Mutation or deregulation of certain cellular genes (protooncogenes) results in expression of proteins that appear to promote malignant transformation. Human non-small cell lung cancer has been documented to express many such oncogenes including c-myc, bcl-2, and mutant p53. Antisense oligodeoxyribonucleotides (ASODN) complementary to these oncogenes were tested on three non-small cell lung cancer cell lines for their efficacy in inhibiting cellular proliferation and oncoprotein expression. Methods.: Established non-small cell lung cancer cell lines A427, SKMES-1, and A549 were grown in the presence of ASODNs complementary to messenger RNA of c-myc, bcl-2, p53, or controls at 1 μmol/L or 10 μmol/L concentrations for 4 or 10 days. Cellular proliferation was measured by tritiated thymidine uptake. Flow cytometry was used to quantitate oncoprotein expression. Intranuclear ASODN uptake was documented by fluoresceinetagged ASODNs. Results.: Fluoresceine-tagged ASODNs were readily taken up by all cell lines. c-myc, as well as bcl-2 and p53 ASODNs, were found to inhibit proliferation of all cell lines significantly compared with controls, most notably in line A549 (40.1% ± 7.1% of control, p = 0.000 with c-myc ASODN). Antisense c-myc reduced c-myc protein by as much as 71.3% in A427, although protein levels were only minimally reduced in the viable cells of the other lines. Conclusions.: c-myc ASODNs inhibit proliferation of non-small cell lung cancer cell lines as well as reduce c-myc protein expression. Antisense bcl-2 and p53 also cause similar growth inhibition. These results suggest a critical role for activation of these oncogenes in the growth of cultured lung cancer cells. Furthermore, the efficacy and rapid cellular uptake of ASODNs support the potential role of antisense targeting of oncogene expression for pharmacologic control of non-small cell lung cancer.

Original languageEnglish (US)
Pages (from-to)1583-1591
Number of pages9
JournalThe Annals of Thoracic Surgery
Volume60
Issue number6
DOIs
StatePublished - Dec 1995

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Antisense Oligodeoxyribonucleotides
Non-Small Cell Lung Carcinoma
Oncogenes
Cell Line
Proto-Oncogene Proteins c-myc
Oncogene Proteins
Cell Proliferation
Growth
Thymidine
Lung Neoplasms
Flow Cytometry
Proteins
Messenger RNA
Mutation

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

c-myc antisense oligodeoxyribonucleotides inhibit proliferation of non-small cell lung cancer. / Robinson, Lary A.; Smith, Larry J.; Fontaine, Michele P.; Kay, H. David; Mountjoy, Charles P.; Pirruccello, Samuel Jay.

In: The Annals of Thoracic Surgery, Vol. 60, No. 6, 12.1995, p. 1583-1591.

Research output: Contribution to journalArticle

Robinson, Lary A. ; Smith, Larry J. ; Fontaine, Michele P. ; Kay, H. David ; Mountjoy, Charles P. ; Pirruccello, Samuel Jay. / c-myc antisense oligodeoxyribonucleotides inhibit proliferation of non-small cell lung cancer. In: The Annals of Thoracic Surgery. 1995 ; Vol. 60, No. 6. pp. 1583-1591.
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title = "c-myc antisense oligodeoxyribonucleotides inhibit proliferation of non-small cell lung cancer",
abstract = "Background.: Mutation or deregulation of certain cellular genes (protooncogenes) results in expression of proteins that appear to promote malignant transformation. Human non-small cell lung cancer has been documented to express many such oncogenes including c-myc, bcl-2, and mutant p53. Antisense oligodeoxyribonucleotides (ASODN) complementary to these oncogenes were tested on three non-small cell lung cancer cell lines for their efficacy in inhibiting cellular proliferation and oncoprotein expression. Methods.: Established non-small cell lung cancer cell lines A427, SKMES-1, and A549 were grown in the presence of ASODNs complementary to messenger RNA of c-myc, bcl-2, p53, or controls at 1 μmol/L or 10 μmol/L concentrations for 4 or 10 days. Cellular proliferation was measured by tritiated thymidine uptake. Flow cytometry was used to quantitate oncoprotein expression. Intranuclear ASODN uptake was documented by fluoresceinetagged ASODNs. Results.: Fluoresceine-tagged ASODNs were readily taken up by all cell lines. c-myc, as well as bcl-2 and p53 ASODNs, were found to inhibit proliferation of all cell lines significantly compared with controls, most notably in line A549 (40.1{\%} ± 7.1{\%} of control, p = 0.000 with c-myc ASODN). Antisense c-myc reduced c-myc protein by as much as 71.3{\%} in A427, although protein levels were only minimally reduced in the viable cells of the other lines. Conclusions.: c-myc ASODNs inhibit proliferation of non-small cell lung cancer cell lines as well as reduce c-myc protein expression. Antisense bcl-2 and p53 also cause similar growth inhibition. These results suggest a critical role for activation of these oncogenes in the growth of cultured lung cancer cells. Furthermore, the efficacy and rapid cellular uptake of ASODNs support the potential role of antisense targeting of oncogene expression for pharmacologic control of non-small cell lung cancer.",
author = "Robinson, {Lary A.} and Smith, {Larry J.} and Fontaine, {Michele P.} and Kay, {H. David} and Mountjoy, {Charles P.} and Pirruccello, {Samuel Jay}",
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T1 - c-myc antisense oligodeoxyribonucleotides inhibit proliferation of non-small cell lung cancer

AU - Robinson, Lary A.

AU - Smith, Larry J.

AU - Fontaine, Michele P.

AU - Kay, H. David

AU - Mountjoy, Charles P.

AU - Pirruccello, Samuel Jay

PY - 1995/12

Y1 - 1995/12

N2 - Background.: Mutation or deregulation of certain cellular genes (protooncogenes) results in expression of proteins that appear to promote malignant transformation. Human non-small cell lung cancer has been documented to express many such oncogenes including c-myc, bcl-2, and mutant p53. Antisense oligodeoxyribonucleotides (ASODN) complementary to these oncogenes were tested on three non-small cell lung cancer cell lines for their efficacy in inhibiting cellular proliferation and oncoprotein expression. Methods.: Established non-small cell lung cancer cell lines A427, SKMES-1, and A549 were grown in the presence of ASODNs complementary to messenger RNA of c-myc, bcl-2, p53, or controls at 1 μmol/L or 10 μmol/L concentrations for 4 or 10 days. Cellular proliferation was measured by tritiated thymidine uptake. Flow cytometry was used to quantitate oncoprotein expression. Intranuclear ASODN uptake was documented by fluoresceinetagged ASODNs. Results.: Fluoresceine-tagged ASODNs were readily taken up by all cell lines. c-myc, as well as bcl-2 and p53 ASODNs, were found to inhibit proliferation of all cell lines significantly compared with controls, most notably in line A549 (40.1% ± 7.1% of control, p = 0.000 with c-myc ASODN). Antisense c-myc reduced c-myc protein by as much as 71.3% in A427, although protein levels were only minimally reduced in the viable cells of the other lines. Conclusions.: c-myc ASODNs inhibit proliferation of non-small cell lung cancer cell lines as well as reduce c-myc protein expression. Antisense bcl-2 and p53 also cause similar growth inhibition. These results suggest a critical role for activation of these oncogenes in the growth of cultured lung cancer cells. Furthermore, the efficacy and rapid cellular uptake of ASODNs support the potential role of antisense targeting of oncogene expression for pharmacologic control of non-small cell lung cancer.

AB - Background.: Mutation or deregulation of certain cellular genes (protooncogenes) results in expression of proteins that appear to promote malignant transformation. Human non-small cell lung cancer has been documented to express many such oncogenes including c-myc, bcl-2, and mutant p53. Antisense oligodeoxyribonucleotides (ASODN) complementary to these oncogenes were tested on three non-small cell lung cancer cell lines for their efficacy in inhibiting cellular proliferation and oncoprotein expression. Methods.: Established non-small cell lung cancer cell lines A427, SKMES-1, and A549 were grown in the presence of ASODNs complementary to messenger RNA of c-myc, bcl-2, p53, or controls at 1 μmol/L or 10 μmol/L concentrations for 4 or 10 days. Cellular proliferation was measured by tritiated thymidine uptake. Flow cytometry was used to quantitate oncoprotein expression. Intranuclear ASODN uptake was documented by fluoresceinetagged ASODNs. Results.: Fluoresceine-tagged ASODNs were readily taken up by all cell lines. c-myc, as well as bcl-2 and p53 ASODNs, were found to inhibit proliferation of all cell lines significantly compared with controls, most notably in line A549 (40.1% ± 7.1% of control, p = 0.000 with c-myc ASODN). Antisense c-myc reduced c-myc protein by as much as 71.3% in A427, although protein levels were only minimally reduced in the viable cells of the other lines. Conclusions.: c-myc ASODNs inhibit proliferation of non-small cell lung cancer cell lines as well as reduce c-myc protein expression. Antisense bcl-2 and p53 also cause similar growth inhibition. These results suggest a critical role for activation of these oncogenes in the growth of cultured lung cancer cells. Furthermore, the efficacy and rapid cellular uptake of ASODNs support the potential role of antisense targeting of oncogene expression for pharmacologic control of non-small cell lung cancer.

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