Chromosome 3 has been implicated in a large number of cancers by karyotypic and loss of heterozygosity studies. The short arm of chromosome 3 is deleted in a variety of cancers, with at least three regions showing maximum loss. In small cell lung cancer, the region 3p21.3 is lost from one homolog in virtually all cases. We have focused on two aspects of this problem: 1) to prove that the gene at 3p21.3 has tumor suppression properties and 2) to clone this gene. In early microcell chromosome transfer studies, we found that an intact chromosome 3 partially suppressed tumor formation in small cell lung cancer. Serendipitously, we found that chromosome 3 could suppress the formation of tumors by mouse A9 fibrosarcoma cells. Furthermore, the region which suppressed tumor growth is a 2 Mb region at 3p21.3. Human sequences from this region by AluPCR were used to screen SCLC lines, and homozygous deletions were found in two lines. A contig of human P1 clones was made of the region. Cotransfection of the P1 clones with a selectable marker into A9 cells narrowed the region which resulted in tumor suppression to 74 Kb. cDNA clones have been isolated from the entire contig and two cDNAs were found to be in the P1 which causes tumor suppression. These cDNAs are being analyzed for mutations in SCLC tumors.