MOLECULAR CHARACTERIZATION OF NEUROENDOCRINE LUNG-TUMORS INDUCED IN HAMSTERS BY TREATMENT WITH NITROSAMINES AND HYPEROXIA

Treatment of hamsters with nitrosamines and hyperoxia (60% O2) induces neuroendocrine lung tumors. Analysis of 8 different tumors from 7 dif ferent hamsters demonstrated 2- to 3.5-fold increases in the expressio n of c-myc in 4 of 8 tumors, c-fos in 3 tumors, c-jun in 1 tumor, c-ra f in 1 tumor, and Ki-ras in 2 tumors. No overexpression of the c-src a nd Ha-ras gene transcripts were detected. Expression levels of N-myc, p53 and the retinoblastoma gene transcript were too low to be quantita ted accurately. In some cases, slightly elevated levels of protooncoge ne transcripts (less than 2-fold) were detected in normal-appearing ti ssue isolated from the same tumor bearing hamsters. Hyperoxia alone ha d little effect on the expression of c-myc or c-fos RNA transcripts co mpared to untreated hamsters. Reverse transcription of the RNAs and am plification of the cDNA copies by the polymerase chain reaction, follo wed by selective oligonucleotide hybridization with normal and mutant probes, did not reveal any mutations in the 12th, 13th, or 61st codons of the seven tumors which produced Ki-ras cDNA. An additional 8 tumor s were also screened for Ki-ras mutations following amplification of g enomic DNA and demonstrated an absence of point mutations at the Ki-ra s gene locus. These results indicate that the hamster neuroendocrine l ung tumors exhibit slight increases in c-myc and c-fos RNA expression but lack mutations at the Ki-ras gene locus.