sdz-psc-833 and Leukemia-P388

Since we discovered verapamil as an MDR-reversing agent in 1981, many MDR-reversing compounds have been reported. This type of drug must be very effective but minimal side effects. We recently found that MS-209 and PSC-833 to be reversing agents that interact directly with P-glycoprotein and show good MDR-reversing effect, both in vitro and in vivo. MS-209 and PSC-833 are thus interesting compounds for clinical use in future.

Topics: Animals; Antineoplastic Agents; Cyclosporins; Doxorubicin; Drug Resistance; Drug Synergism; Humans; Leukemia P388; Mice; Quinolines; Verapamil

Conventional methods that are used to overcome multidrug resistance (MDR) often involve the coadministration of chemosensitizers and anticancer drugs. The cyclosporin analogue SDZ PSC 833 [(3'-keto-Bmt1)-(Val2)-cyclosporin] (PSC 833) has been shown to possess powerful chemosensitization properties in vitro, in addition to being intrinsically nontoxic. However, coadministration of PSC 833 with anticancer drugs, such as daunorubicin, doxorubicin (DOX), and Taxol, have resulted in the exacerbation of anticancer drug toxicity, which is due to altered anticancer drug pharmacokinetics. Here, we hypothesized that optimization of the anticancer drug delivery, using liposomal carriers, may, by avoiding these adverse interactions, offer a significant advantage over nonencapsulated drugs. Toxicity studies were conducted in normal BDF1 mice, with i.v. DOX (free or liposome encapsulated) administration and p.o. PSC 833 in single and multiple dosage regimens over a 15-day study period. p.o. administration of PSC 833, at a dose of 100 mg/kg, reduced the maximum tolerated dose (MTD) of i.v administered free drug by 2.5-3-fold, in single- and multiple-dose regimens. In contrast, PSC 833 administration resulted in only a 20% reduction of the MTD for DOX encapsulated in 100-nm 1,2 distearoyl-sn-glycero-3-phosphocholine/cholesterol liposomes (55:45 molar lipid ratio) in a single-dose regimen and had no effect on the liposomal DOX MTD for the day 1, 5, and 9 treatment schedule. Modest modulation of P-glycoprotein-mediated MDR was observed in the murine P388/ADR solid tumor model when PSC 833 was administered with free DOX at the MTD. In contrast, liposomal DOX combined with PSC 833 resulted in tumor growth inhibition that was comparable to that observed for drug-sensitive P388/WT tumors. This efficacy of P388/ADR tumors treatment was dependent on PSC 833 because treatment with liposomal DOX alone provided significantly less antitumor activity. Pharmacokinetic and tissue distribution data demonstrated that DOX encapsulated in 1,2 distearoyl-sn-glycero-3-phosphocholine/cholesterol liposomes exhibited comparable plasma elimination and tissue distribution properties in the presence and absence of PSC 833, whereas free DOX displayed reduced plasma elimination rates and altered tissue distribution in the presence of PSC 833. These results provide evidence that PSC 833 can induce P-glycoprotein modulation and chemosensitize MDR tumors in the absence of altered DOX pharmacokinetics w

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cholesterol; Cyclosporins; Doxorubicin; Drug Carriers; Drug Resistance, Multiple; Female; Leukemia P388; Liposomes; Metabolic Clearance Rate; Mice; Phosphatidylcholines; Tissue Distribution

Two methods based on the reversion of adriamycin-resistance o the increase of Rhodamine 123 accumulation in a multidrug resistant (MDR) cell line have been simplified and adapted for the screening of MDR reversal agents. Both methods are carried out in microtiter plates, are highly sensitive and can be easily automated. In both assays verapamil and the cyclosporine derivative PSC 833 could be detected at concentrations lower than 1 and 0.05 microM, respectively. Depending on the MDR cell line used, drugs exhibiting the collateral sensitivity phenomenon can be selected in the cytotoxicity assay, while interferences due to sample toxicity are easily avoided in the dye accumulation assay.

Topics: Adenocarcinoma; Animals; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Colonic Neoplasms; Cyclosporins; Doxorubicin; Drug Resistance, Multiple; Drug Screening Assays, Antitumor; Fluorescent Dyes; Humans; Leukemia P388; Mice; Rhodamine 123; Rhodamines; Verapamil

SDZ PSC 833 (PSC 833) is a non-immunosuppressive analogue of cyclosporin A and is a potent modifier of P-glycoprotein (P-gp)-mediated multidrug resistance. The present study was undertaken to evaluate whether doxorubicin (DOX) pharmacokinetic and anti-tumour activity on P388- and P388/DOX-resistant leukaemia was modified by PSC 833 pretreatment. P388- or P388/DOX-bearing mice were given PSC 833 intraperitoneally 30 min before an intravenous injection of DOX. The levels of DOX were determined by a high-performance liquid chromatography method in leukaemic cells and in normal tissues (heart, lung, liver, small intestine, kidney and spleen). In all tissues, DOX concentrations were significantly increased in mice pretreated with PSC 833. The difference was greatest in P-gp-overexpressing P388/DOX cells, the DOX area under the curve being approximately seven times greater after PSC 833 and DOX than after DOX alone. In P388 cells the difference was approximately 2.5 times, as in the majority of normal tissues. As expected DOX levels in P388 cells were higher than in P388/DOX cells in mice treated with DOX alone, whereas after PSC 833 and DOX the levels of DOX were similar in the two leukaemic lines. In spite of this PSC 833 was unable to reverse the resistance to DOX of P388/DOX leukaemia in vivo, suggesting that mechanisms other than P-gp expression are responsible for resistance.

Topics: Animals; Antibiotics, Antineoplastic; ATP-Binding Cassette Transporters; Blotting, Northern; Cyclosporins; Doxorubicin; Drug Interactions; Drug Resistance; Leukemia P388; Male; Mice; Mice, Inbred Strains; Multidrug Resistance-Associated Proteins; Tissue Distribution

Although verapamil, cyclosporin A. cremophor EL and PSC-833 are active as multidrug resistance modulators, there has been limited study of these compounds as possible chemotherapy enhancing agents against drug-sensitive tumors. We compared these agents as modifiers of VP-16 cytotoxicity in vitro and modifiers of VP-16 efficacy in vivo against drug-sensitive P388 and L1210 leukemias. Our study indicates that cyclosporin A enhances VP-16 cytotoxicity to a significantly greater extent than equimolar concentrations of verapamil or PSC-833. Although cremophor EL shows significantly greater activity than verapamil in VP-16 cytotoxicity enhancement in vitro, it is ineffective when added to VP-16 therapy of mice bearing L1210 leukemia.

Topics: Animals; Cell Survival; Cyclosporine; Cyclosporins; Drug Synergism; Etoposide; Glycerol; Leukemia L1210; Leukemia P388; Mice; Survival Analysis; Tumor Cells, Cultured; Verapamil

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

The new nonimmunosuppressive cyclosporin analogue, SDZ PSC 833, is a very potent multidrug-resistance modifier. In vitro, it was shown to be at least 10-fold more active than cyclosporin A (Sandimmune), itself more active than verapamil, on most P-glycoprotein-expressing multidrug-resistant (MDR) tumor cell lines. In vivo, SDZ PSC 833 was tested in a few protocols of combined therapy with either Vinca alkaloids or doxorubicin as anticancer drugs, using the homologous tumor-host system (P388 cells of DBA/2 origin grafted into DBA/2 or B6D2F1 mice). Although these MDR-P388 tumor cells belong to a highly resistant variant that in vitro required about 150-fold more anticancer drug for 50% cell growth inhibition than the parental P388 cells, significant prolongation of survival times of the MDR-P388 tumor-bearing mice was obtained when treated with a combination of SDZ PSC 833 p.o. were otherwise ineffective doses of anticancer drugs given i.p. This chemosensitizing effect of SDZ PSC 833 was dose-dependent and was most effective in a protocol combining administration of SDZ PSC 833 p.o. 4 h before a doxorubicin i.p. injection: in comparison with the survival of MDR-P388 tumor-bearing mice treated with the anticancer drug alone, the pretreatment with SDZ PSC 833 at 25 and 50 mg/kg gave 2- to 3-fold increases of survival times. Since the MDR-P388 tumor cells used in our studies belong to a highly resistant variant, with a much higher degree of drug resistance than the one known to occur in cancer patients, SDZ PSC 833 appears to be a very promising chemosensitizer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Survival; Cyclosporins; Dose-Response Relationship, Drug; Drug Resistance; Leukemia P388; Membrane Glycoproteins; Mice; Mice, Inbred DBA; Mice, Inbred Strains