抄録
Aromatic hydrocarbon carcinogens, 7, 12-dimethylbenz [a] anthacene (DMBA) and 7, 8, 12-trimethylbenz [a] anthracene (TMBA) induce leukemia in the rat. Almost 30% of DMBA- and 16% of TMBA-induced leukemia reveal total or partial trisomy of #2 chromosome (+2 and 2q+, respectively) and many of the rest have normal diploid (2n) karyotype. Most of these leukemias are erythroblastic leukemia and they reveal a specific mutation of N-ras gene (A → T transversion at the second base of colon 61) . N-ras gene was assigned to chromosome band 2q34 in a commonly duplicated segment of +2 and 2q+. Although the 2n leukemias with N-ras mutation reveal loss of wild type N-ras allele (LOH), the +2 leukemias retain the wild type allele. This means that +2, 2q+, and LOH contribute to the dominancy of mutant N-ras gene.
This article reviews the general aspects of DMBA- and TMBA-induced rat leukemias focusing on the origin of the specific N-ras mutation and other specific genetic changes in leukemia cells.
DMBA and TMBA induce chromosome aberrations (CA) non-randomly distributed along chromosomes. Three major susceptible regions were found along the #2 chromosome including the N-ras locus. Some marker chromosomes in leukemias, 3 types of 2q+ and one of translocation type +2, had chromatid structures obviously formed by chromosome rearrangements at these DMBA-susceptible sites. The role of rDNA loci on #3, #11, and #12 chromosomes and some oncogenes (abl and H-ras) in translocations was also shown in leukemia cells. The susceptibility of the above chromosome regions to DMBA was markedly enhanced by erythropoietin (Ep) given a short time before DMBA treatment. The incidence of DMBA-leukemia was also enhanced by the preliminary anemia treatment. From these results, the authors propose that the change in susceptibility of target cells to chemical carcinogens is caused by transcription induced by Ep allowing the preferential binding of active carcinogen-metabolites to the specific genomic sites. Gene induction is therefore considered an essential step in carcinogenesis.
