Mouse leukemia P388 sublines that acquired the resistance to multiple drugs as a result of treatment in vivo with anthracyclines (rubomycin, ruboxyl) and/or vincristine were studied. The mdr gene amplification was found in all tested cell lines: in four of five sublines all three members of the mdr gene family showed increased copy numbers, and in one cell line, developed after treatment with ruboxyl, mdr1a and mdr1b genes were amplified to the same degree, whereas the mdr2 gene was not amplified at all. The levels of amplification of mdr genes varied in different cell lines from 30-fold to 50-fold. Unusual cytological manifestations--relatively large newly formed chromosomelike structures, were revealed in four of five long-term independent sublines. Some of these structures did not contained C blocks; the others, in contrast, were enriched by C-heterochromatin. In situ hybridization showed the presence of mdr genes in newly formed bodies. In the majority of cases, the formation of chromosomelike structures was preceded by the appearance of other, smaller size, structures: the so-called "small chromatin bodies" (minichromosomes) and/or homogeneously G-positive small ring chromosomes.