Nuclear morphological alterations associated with multidrug resistance (MDR) were evaluated by image cytometry in various human leukemic cell sub-lines: 3 cell lines with P-gp-mediated resistance (CEM-VLB, HL6O/Vinc, K562-Dox), the non-Pgpmediated MDR HL6O/AR leukemic cell line with over-expression of MRP, and the at-MDR CEM-VM I leukemic cell line with alteration of topoisomerase II. All these MDR cell sub-lines were obtained by drug selection and were compared with their sensitive counterparts and with the hamster LR73-R cell line obtained by transfection of mouse mdrl cDNA. All MDR cell sub-lines obtained by drug selection displayed decreased DNA Feulgen stainability as compared with their respective sensitive parental cell line, a phenomenon not observed in the transfected LR73-R cells. Nuclear texture analysis on Go/G,-selected cell nuclei revealed 2 types of textural phenotype. The first phenotype was characterized by chromatin decondensation with small but compact chromatin clumps, and was observed in drug-selected P-gp-mediated MDR cells (CEM-VLB, HL6O-Vinc, K562-Dox) and in the non-P-gp-mediated MDR HL60IAR cell line. The second phenotype was characterized by a condensed and homogeneous chromatin pattern, and was observed in the at-MDR CEM-VM I cell line. LR73-R cells transfected with mdr I cDNA did not display any significant changes in textural phenotype as compared with sensitive LR73 cells, suggesting that P-gp over-expression alone cannot account for the cytological modifications observed in MDR cells. These data suggest that multidrug resistance could be associated with specific nuclear morphological changes which appeared to be a consequence of alterations occurring during selection by cytotoxic drugs rather than of P-p over-expression.
o I995 Wi&-Liss, Inc.