M. Michieli et al., P170-DEPENDENT MULTIDRUG-RESISTANCE - RESTORING FULL SENSITIVITY TO IDARUBICIN WITH VERAPAMIL AND CYCLOSPORINE-A DERIVATIVES, Haematologica, 79(2), 1994, pp. 119-126
Background. Cell sensitivity to anthracyclines and other drugs depends
on several factors, including overexpression of a 170Kd transmembrane
glycoprotein (P170) that enhances drug efflux from the cells. Since t
he result of treatment is negatively related to the expression of P170
in leukemia, malignant lymphoma and other tumors, it is important to
investigate drugs and methods that can modify multidrug resistance (MD
R). Materials and Methods. Using an MTT-microcultured tetrazolium colo
rimetric method, we assayed sensitivity to daunorubicin (DNR) and to i
ts 4-demethoxy derivative idarubicin (IDA) in two MDR cell lines (CEM
VLB and LOVO DX) and in their respective non-MDR parental lines (CEM a
nd LOVO 109), with and without three MDR modifiers, namely the D-isome
r of verapamil (DVRP), cyclosporin A (CyA) and the new CyA derivative
SDZ PSC 833. Results. We showed that down-modulation of resistance wit
h MDR modifiers was greater for DNR than for IDA in MDR cells. However
, we also demonstrated that restoration of full sensitivity could only
be achieved for IDA, not for DNR. DVRP and CyA in combination were mo
re effective than either compound alone and could abolish P170-related
resistance to IDA at concentrations of 1-2 mu M and 1.6 mu M, respect
ively SDZ PSC 833 alone was even more effective and set MDR to Zero at
a concentration ranging between 0.8 and 1.6 mu M. Conclusions. These
data suggest that combinations of IDA and MDR modifiers may improve th
e results of cancer and leukemia treatment and that they are worth inv
estigating in vivo, with attention to possible effects on drug pharmac
okinetics and on normal tissue damage.