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 different hamsters demonstrated 2- to 3.5-fold increases in the expression of c-myc in 4 of 8 tumors, c-fos in 3 tumors, c-jun in 1 tumor, c-raf in 1 tumor, and Ki-ras in 2 tumors. No overexpression of the c-src and Ha-ras gene transcripts were detected. Expression levels of N-myc, p53 and the retinoblastoma gene transcript were too low to be quantitated accurately. In some cases, slightly elevated levels of protooncogene transcripts (less than 2-fold) were detected in normal-appearing tissue isolated from the same tumor bearing hamsters. Hyperoxia alone had little effect on the expression of c-myc or c-fos RNA transcripts compared to untreated hamsters. Reverse transcription of the RNAs and amplification of the cDNA copies by the polymerase chain reaction, followed 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 tumors were also screened for Ki-ras mutations following amplification of genomic DNA and demonstrated an absence of point mutations at the Ki-ras gene locus. These results indicate that the hamster neuroendocrine lung tumors exhibit slight increases in c-myc and c-fos RNA expression but lack mutations at the Ki-ras gene locus.