C-MYC ANTISENSE OLIGODEOXYRIBONUCLEOTIDES INHIBIT PROLIFERATION OF NON-SMALL-CELL LUNG-CANCER

Background. Mutation or deregulation of certain cellular genes (protoo ncogenes) results in expression of proteins that appear to promote mal ignant transformation. Human non-small cell lung cancer has been docum ented to express many such oncogenes including c-myc, bcl-2, and mutan t p53. Antisense oligodeoxyribonucleotides (ASODN) complementary to th ese oncogenes were tested on three non-small cell lung cancer cell lin es for their efficacy in inhibiting cellular proliferation and oncopro tein expression. Methods. Established non-small cell lung cancer cell Lines A427, SKMES-1, and A549 were grown in the presence of ASODNs com plementary to messenger RNA of c-myc, bcl-2, p53, or controls at 1 mu mol/L or 10 mu mol/L concentrations for 4 or 10 days. Cellular prolife ration was measured by tritiated thymidine uptake. Flow cytometry was used to quantitate oncoprotein expression. Intranuclear ASODN uptake w as documented by fluoresceine-tagged ASODNs. Results. Fluoresceine-tag ged 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-m yc 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 l ines. Conclusions. c-myc ASODNs inhibit proliferation of non-small cel l lung cancer cell lines as well as reduce c-myc protein expression. A ntisense bcl-2 and p53 also cause similar growth inhibition. These res ults suggest a critical role for activation of these oncogenes in the growth of cultured lung cancer cells. Furthermore, the efficacy and ra pid cellular uptake of ASODNs support the potential role of antisense targeting of oncogene expression for pharmacologic control of non-smal l cell lung cancer.