SENSITIVITY OF K562 HUMAN CHRONIC MYELOGENOUS LEUKEMIA BLAST CELLS TRANSFECTED WITH A HUMAN MULTIDRUG-RESISTANCE CDNA TO CYTOTOXIC DRUGS AND DIFFERENTIATING AGENTS
Wn. Hait et al., SENSITIVITY OF K562 HUMAN CHRONIC MYELOGENOUS LEUKEMIA BLAST CELLS TRANSFECTED WITH A HUMAN MULTIDRUG-RESISTANCE CDNA TO CYTOTOXIC DRUGS AND DIFFERENTIATING AGENTS, The Journal of clinical investigation, 91(5), 1993, pp. 2207-2215
The blast crisis of chronic myelogenous leukemia (CML) is refractory t
o most forms of cancer chemotherapy, but may be amenable to drugs that
differentiate rather than kill leukemic cells. One mechanism implicat
ed in resistance to cytodestructive drugs is overexpression of P-glyco
protein, the MDR1 gene product. While several classes of drugs sensiti
ze multidrug-resistant (MDR) cells by interfering with the function of
P-glycoprotein in vitro, few sensitizers have been effective in vivo.
We have developed a preclinical model of MDR/CML uncomplicated by oth
er mechanisms of drug resistance to evaluate the effects of MDR1 overe
xpression on cytodestructive and differentiation therapy and the abili
ty of sensitizers to restore chemosensitivity in this disease. The CML
-derived cell line K562 was transfected with a human MDR1 cDNA from th
e pHaMDR1/A expression vector and selected with vinblastine. Resistant
K562 clones were 20-30-fold resistant to vinblastine, were cross-resi
stant to doxorubicin and etoposide, and remained sensitive to cytosine
arabinoside, 6-thioguanine, hydroxyurea, and mechlorethamine. Resista
nce was associated with decreased cellular accumulation of cytotoxic d
rug and was reversed by cyclosporin A and trans-flupenthixol. The MDR
phenotype did not adversely affect the ability of K562 cells to produc
e fetal hemoglobin in response to hemin, and was associated with incre
ased responsiveness of cells to differentiate with cytosine arabinosid
e. Upon differentiation, the resistant clones increased MDR1 mRNA and
P-glycoprotein. These studies suggest that the overexpression of the M
DR1 gene in CML may not adversely affect the ability to undergo erythr
oid differentiation and that these resistant K562 cell lines are good
models for studying drug resistance mediated by P-glycoprotein in CML.