NUCLEAR-DNA CONTENT AND CHROMATIN TEXTURE IN MULTIDRUG-RESISTANT HUMAN LEUKEMIC-CELL LINES

Nuclear morphological alterations associated with multidrug resistance (MDR) were evaluated by image cytometry in various human leukemic cel l sub-lines: 3 cell lines with P-gp-mediated resistance (CEM-VLB, HL60 /Vinc, K562-Dox), the non-Pgp-mediated MDR HL60/AR leukemic cell line with over-expression of MRP, and the at-MDR CEM-VM I leukemic cell lin e with alteration of topoisomerase II. All these MDR cell sob-lines we re obtained by drug selection and were compared with their sensitive c ounterparts and with the hamster LR73-R cell line obtained by transfec tion of mouse mdr 1 cDNA. All MDR cell sub-lines obtained by drug sele ction displayed decreased DNA Feulgen stainability as compared with th eir respective sensitive parental cell line, a phenomenon not observed in the transfected LR73-R cells. Nuclear texture analysis on G(0)/G(1 )-selected cell nuclei revealed 2 types of textural phenotype. The fir st phenotype was characterized by chromatin decondensation with small but compact chromatin clumps, and was observed in drug-selected P-gp-m ediated MDR cells (CEM-VLB, HL6O-Vinc, K562-Dox) and in the non-P-gp-m ediated MDR HL60/AR 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 1 cDN A did not display any significant changes in textural phenotype as com pared 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 associat ed with specific nuclear morphological changes which appeared to be a consequence of alterations occurring during selection by cytotoxic dru gs rather than of P-gp over-expression. (C) 1995 Wiley-Liss, Inc.