Jd. Allen et al., Extensive contribution of the multidrug transporters P-glycoprotein and Mrp1 to basal drug resistance, CANCER RES, 60(20), 2000, pp. 5761-5766
Despite accumulating evidence that multidrug resistance transporter protein
s play a part in drug resistance in some clinical cancers, it remains uncle
ar whether the relatively low levels of multidrug resistance transporter ex
pression found in most untreated tumors could substantially affect their ba
sal sensitivity to antineoplastic drugs. To shed light on this problem, the
drug sensitivities of wild-type mouse cell lines were compared with those
of lines in which the A Mdr1a and Mdr1b genes encoding P-glycoprotein (P-gp
) were inactivated and lines in which the Mrp1 gene was inactivated in addi
tion to Mdr1a and Mdr1b. These models permit a clean dissection of the cont
ribution of each transporter to drug resistance at expression levels simila
r to those in normal tissues and avoid complications that might arise from
previous exposure of cell lines to drug selection. For substrate drugs, we
found that these contributions can indeed be very substantial, Lines lackin
g functional P-gp were, on average, markedly more sensitive to paclitaxel (
16-fold), anthracyclines (4-fold) and Vinca alkaloids (3-fold). Lines lacki
ng both P-gp and Mrp1 were (compared with wild-type lines) hypersensitive t
o an even broader array of drugs, including epipodophyllotoxins ( 4-7-fold)
, anthracyclines (6-7-fold), camptothecins (3-fold), arsenite (il-fold) and
Vinca alkaloids, especially vincristine (28-fold), Thus, even very low lev
els of P-gp and Mrp1 expression that may be difficult to detect in tumors c
ould significantly affect their innate sensitivity to a wide range of clini
cally important substrate drugs. An implication is that the use of resistan
ce reversal agents to sensitize drug-naive tumors may be appropriate in mor
e cases than is presently appreciated.