sdz-280-446 and Leukemia-P388

The low daunomycin (DAU) retention in P388 cells displaying P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) can be increased by the presence of various resistance-modifying agents (RMAs). Taking the DAU retention restoration as an indicator of Pgp function inhibition and using a few RMAs, including SDZ PSC 833, SDZ 280-446, cyclosporin A (CsA) and verapamil, we compared different conditions of MDR cell exposure to the RMA. The 'co + post-RMA' treatments (RMA present during both DAU uptake and efflux phases) generally led to higher DAU retention levels than the 'co-RMA' treatments (RMA present during the DAU uptake phase only). The magnitude and persistence of Pgp function inhibition induced by the RMA was further examined by only pulsing the cells with the RMA and growing them in RMA-free medium before the DAU retention assay ('pre-RMA' treatment). While recovery of Pgp function was nearly complete within minutes after a pulse exposure to verapamil, this took increasing times with CsA, SDZ 280-446 and SDZ PSC 833, the latter RMA leaving traces of inhibition of Pgp function even 2 days after the pulse exposure of the MDR-P388 cells. The persistence of Pgp inhibition conferred by some RMAs being much longer than by others, this feature should be taken into account when designing chemotherapy protocols in the clinic.

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carrier Proteins; Cyclosporine; Cyclosporins; Daunorubicin; Drug Resistance; Extracellular Space; Leukemia P388; Membrane Glycoproteins; Mice; Molecular Sequence Data; Peptides, Cyclic; Verapamil

Taxol, a promising agent for the treatment of cancer, has entered phase II clinical trials. Nevertheless, it belongs to the class of compounds that show impaired retention in multidrug-resistant cells expressing P-glycoprotein (Pgp), a drug efflux pump. Chemosensitizers like verapamil modulate multidrug resistance by interfering with the efflux action of Pgp and thus can decrease drug resistance or can restore drug sensitivity by restoring normal drug accumulation and distribution within the multidrug-resistant tumor cell. The two strongest, nearly equipotent chemosensitizers identified to date are the cyclosporine derivative SDZ PSC 833 and the semisynthetic cyclopeptolide SDZ 280-446.. This study was designed to investigate the capacities of verapamil, SDZ PSC 833, and SDZ 280-446 to decrease resistance of two multidrug-resistant cell lines to taxol.. We studied in vitro the growth of two multidrug-resistant tumor cell lines displaying high resistance to taxol: multidrug-resistant Chinese hamster ovary cells and murine monocytic leukemia P388 cells. We determined the taxol concentration that produced 50% inhibition of cell growth (IC50) in the two multidrug-resistant cell lines and in the parent cell lines, in the presence of a range of chemosensitizer concentrations (0-30 microM). IC50 values were determined in the presence and in the absence of verapamil, SDZ PSC 833, or SDZ 280-446.. At nontoxic concentrations (0.3-1 microM), SDZ PSC 833 and SDZ 280-446 produced an almost complete reversal of the high taxol resistance of the multidrug-resistant tumor cells, whereas only partial restoration of sensitivity to taxol was achieved with verapamil.. SDZ PSC 833 and SDZ 280-446 can restore the normal taxol sensitivity of highly resistant multidrug-resistant tumor cells.. The combination of taxol with SDZ PSC 833 or SDZ 280-446 may be recommended for treatment of multidrug-resistant cancers.

Topics: Animals; Antineoplastic Agents; CHO Cells; Cricetinae; Cyclosporins; Drug Resistance; Leukemia P388; Mice; Paclitaxel; Peptides, Cyclic; Tumor Cells, Cultured; Verapamil