Relationship between the intracellular daunorubicin concentration, expression of major vault protein/lung resistance protein and resistance to anthracyclines in childhood acute lymphoblastic leukemia
Ml. Den Boer et al., Relationship between the intracellular daunorubicin concentration, expression of major vault protein/lung resistance protein and resistance to anthracyclines in childhood acute lymphoblastic leukemia, LEUKEMIA, 13(12), 1999, pp. 2023-2030
In vitro resistance to anthracyclines is related to a poor prognosis in chi
ldhood acute lymphoblastic leukemia (ALL), but the underlying mechanisms ar
e poorly understood. Using flow cytometry, we studied the contribution of d
aunorubicin (DNR) accumulation and retention, cell size, expression of the
major vault protein/lung resistance protein (LRP), P-glycoprotein (P-gp) an
d multidrug resistance-associated protein (MRP) to the cytotoxicity of DNR
(by MTT assay) in childhood ALL. The accumulated and retained DNR content w
as not related to the degree of DNR resistance, nor did the content differ
between 53 initial and 20 relapse ALL samples (P > 0.05), although the latt
er were median two-fold more resistant to DNR (P = 0.004), Leukemic cell vo
lume correlated with resistance to the anthracyclines DNR (Rs 0.32, P = 0.0
12) and idarubicin (Rs 0.46, P = 0.011) but not to other classes of drugs s
uch as prednisolone, vincristine, L-asparaginase and etoposide. Relapsed pa
tients had 1.5-fold larger cells than patients at initial diagnosis of ALL
(P = 0.001). After cell volume correction, the intracellular DF IR concentr
ation was lower in relapsed compared with initial ALL cells (eg 60 min accu
mulation, P = 0.003). Moreover, the intracellular DNR concentration inverse
ly correlated with DNR resistance, both in the accumulation (Rs -0.44, P <
0.001) and retention (Rs -0.33, P = 0.016) test condition. The accumulated
DNR concentration inversely correlated with expression of LRP (Rs -0.36, P
= 0.012) but not with P-gp and MRP. Expression of LRP, but not of P-gp and
MRP, significantly correlated with DNR resistance in childhood ALL (Rs 0.33
, P = 0.03). In conclusion, the intracellular DNR concentration and the exp
ression level of LRP may contribute to DNR resistance in childhood ALL. The
strength of the correlations also indicates that resistance to anthracycli
nes can not be explained by one single mechanism.