Comparative Study on Reversal Efficacy of SDZ PSC 833, Cyclosporin a and Verapamil on Multidrug Resistance in vitro and in vivo

1995 ◽  
Vol 34 (2) ◽  
pp. 235-241 ◽  
Author(s):  
Toru Watanabe ◽  
Harumi Tsuge ◽  
Tomoko Oh-Hara ◽  
Mikihiko Naito ◽  
Takashi Tsuruo
Keyword(s):  
Multidrug Resistance ◽  
Comparative Study ◽  
Cyclosporin A ◽  
Psc 833 ◽  
Sdz Psc 833

Cyclosporin A and cyclosporin SDZ PSC 833 enhance anti-CD5 ricin A- chain immunotoxins in human leukemic T cells

Blood ◽  
1994 ◽  
Vol 83 (2) ◽  
pp. 482-489 ◽  
Author(s):  
JP Jaffrezou ◽  
BI Sikic ◽  
G Laurent
Keyword(s):  
Cyclosporin A ◽  
Small Population ◽  
High Dose ◽  
Ricin A Chain ◽  
Psc 833 ◽  
A Chain ◽  
Ricin A ◽  
Sdz Psc 833

Abstract Recent studies have shown that cyclosporin A (CsA) may affect ricin A- chain immunotoxin (RTA-IT) therapy. In this study, we evaluated the ability of CsA and its nonimmunosuppressive analog, SDZ PSC 833, to enhance anti-CD5 T101 RTA-ITs in vitro. Both 4 mumol/L CsA and 4 mumol/L SDZ PSC 833 significantly and specifically enhanced the cytotoxic activity of T101 RTA-IT on the human lymphoblastic T-cell line, CEM III (101-fold and 105-fold, respectively). Furthermore, these Cs also enhanced the cytotoxicity of the more potent T101 F(ab')2 RTA- IT (ninefold and eightfold, respectively). The effect of human plasma, originating from four patients enrolled in a phase I high-dose CsA regimen, was examined on T101 RTA-IT cytotoxicity on CEM III cells. In each case, with plasma CsA levels between 3,090 and 4,860 ng/mL (2.5 to 4 mumol/L), a significant increase in T101 RTA-IT-mediated cytotoxicity was observed ranging from 31% to 60%. Neither CsA nor SDZ PSC 833 affected the rate of RTA-IT binding, internalization, intracellular trafficking, or degradation. Analysis of internalized T101 RTA-IT molecules showed that these were essentially intact, which suggests that these enhancers may act only on a small population of RTA-ITs that escapes present investigational techniques. In conclusion, because the concentrations used are clinically achievable, Cs appear to be promising agents for in vivo enhancement of RTA-ITs.

scholarly journals Cyclosporin A and cyclosporin SDZ PSC 833 enhance anti-CD5 ricin A- chain immunotoxins in human leukemic T cells

Blood ◽  
1994 ◽  
Vol 83 (2) ◽  
pp. 482-489
Author(s):  
JP Jaffrezou ◽  
BI Sikic ◽  
G Laurent
Keyword(s):  
Cyclosporin A ◽  
Small Population ◽  
High Dose ◽  
Ricin A Chain ◽  
Psc 833 ◽  
A Chain ◽  
Ricin A ◽  
Sdz Psc 833

Recent studies have shown that cyclosporin A (CsA) may affect ricin A- chain immunotoxin (RTA-IT) therapy. In this study, we evaluated the ability of CsA and its nonimmunosuppressive analog, SDZ PSC 833, to enhance anti-CD5 T101 RTA-ITs in vitro. Both 4 mumol/L CsA and 4 mumol/L SDZ PSC 833 significantly and specifically enhanced the cytotoxic activity of T101 RTA-IT on the human lymphoblastic T-cell line, CEM III (101-fold and 105-fold, respectively). Furthermore, these Cs also enhanced the cytotoxicity of the more potent T101 F(ab')2 RTA- IT (ninefold and eightfold, respectively). The effect of human plasma, originating from four patients enrolled in a phase I high-dose CsA regimen, was examined on T101 RTA-IT cytotoxicity on CEM III cells. In each case, with plasma CsA levels between 3,090 and 4,860 ng/mL (2.5 to 4 mumol/L), a significant increase in T101 RTA-IT-mediated cytotoxicity was observed ranging from 31% to 60%. Neither CsA nor SDZ PSC 833 affected the rate of RTA-IT binding, internalization, intracellular trafficking, or degradation. Analysis of internalized T101 RTA-IT molecules showed that these were essentially intact, which suggests that these enhancers may act only on a small population of RTA-ITs that escapes present investigational techniques. In conclusion, because the concentrations used are clinically achievable, Cs appear to be promising agents for in vivo enhancement of RTA-ITs.

Clinical modulation of multidrug resistance in multiple myeloma: effect of cyclosporine on resistant tumor cells.

1994 ◽  
Vol 12 (8) ◽  
pp. 1584-1591 ◽  
Author(s):  
P Sonneveld ◽  
M Schoester ◽  
K de Leeuw
Keyword(s):  
Multiple Myeloma ◽  
Multidrug Resistance ◽  
Efflux Pump ◽  
Clinical Treatment ◽  
Drug Efflux ◽  
Intracellular Accumulation ◽  
Psc 833 ◽  
Clinical Resistance ◽  
Sdz Psc 833

PURPOSE In multiple myeloma (MM) refractory to doxorubicin (DXR) and/or vincristine (VCR), myeloma cells frequently express the multidrug resistance (MDR) phenotype, associated with overexpression of P-glycoprotein (Pgp), which acts as a drug efflux pump. Recently, studies have shown that clinical resistance can be modulated by drug resistance modifiers. The present study was performed to investigate if MDR modulation in vivo is caused by a direct effect of cyclosporine (CSA) on resistant myeloma plasma cells (PC). PATIENTS AND METHODS Eight patients with VAD-refractory MM were treated with DXR, VCR, and dexamethasone (VAD) plus CSA. Pgp expression in PC was determined by flow cytometry/immunocytochemistry before and after clinical treatment. Functional Pgp expression was determined by the effect of CSA on the intracellular accumulation of DXR and VCR. RESULTS Five of eight patients responded to VAD/CSA. The percentage of Pgp-positive (Pgp+) PC was 30% to 100% (median, 90%) before treatment and 4 to 90% (median, 40%) after treatment. CD56+/- or CD38+/- PC had identical Pgp expression. CSA, as well as SDZ PSC 833, but not dexamethasone, increased pretreatment intracellular accumulation of DXR and VCR in Pgp+ PC in three of four and six of six patients, respectively. After clinical treatment, in vitro drug accumulation in residual Pgp-negative (Pgp-) PC of four of four responding patients was not further modulated by CSA or SDZ PSC 833. At later relapse, PC of two of four patients remained Pgp-. CONCLUSION These data indicate that Pgp overexpression is functional in refractory myeloma and that clinical modulation of MDR by CSA is mediated through an inhibition of Pgp-associated drug efflux. Pgp-expressing PC can be eliminated by clinical treatment with VAD/CSA.

scholarly journals Gene transfer of multidrug resistance into a factor-dependent human hematopoietic progenitor cell line: in vivo model for genetically transferred chemoprotection

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 2723-2731 ◽  
Author(s):  
P Schwarzenberger ◽  
S Spence ◽  
N Lohrey ◽  
T Kmiecik ◽  
DL Longo ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Gene Transfer ◽  
Hematopoietic Progenitor Cells ◽  
Mdr1 Gene ◽  
In Vivo Model ◽  
Hematopoietic Progenitor ◽  
Human Dna

To develop a rapid preclinical in vivo model to study gene transfer into human hematopoietic progenitor cells, MO-7e cells (CD-34+, c-kit+) were infected with multidrug resistance (MDR1)-containing retroviruses and then transplanted into nonobese diabetic severe combined immunodeficient mice (NOD SCID). MO-7e cells infected with a retrovirus encoding the human MDR1 cDNA showed integration, transcription, and expression of the transfered MDR1 gene. This resulted in a 20-fold increase in the resistance of MO-7e cells to paclitaxel in vitro. The expression of the MDR1 gene product was stable over a 6-month period in vitro without selection in colchicine. MO-7e and MDR1-infected MO-7e cells were transplanted into NOD SCID mice to determine whether MDR1 could confer drug resistance in vivo. A sensitive polymerase chain reaction method specific for human sequences was developed to quantitate the level of human cell engraftment in NOD SCID bone marrow (BM) cells. The percentage of human DNA in BM cells from MO-7e- transplanted mice was 10.9% and decreased to 0.7% in mice treated with paclitaxel. The percentage of human DNA in infected-MO-7e transplanted mice was 7.6% and that level was unchanged in mice treated with paclitaxel. These results show that expression of the MDR1 gene in human hematopoietic progenitor cells can confer functional drug resistance in an in vivo model.

scholarly journals Overcoming multidrug-resistance in vitro and in vivo using the novel P-glycoprotein inhibitor 1416

2012 ◽  
Vol 32 (6) ◽  
pp. 559-566 ◽  
Author(s):  
Yan Xu ◽  
Feng Zhi ◽  
Guangming Xu ◽  
Xiaolei Tang ◽  
Sheng Lu ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Chemotherapy ◽  
Antitumour Activity ◽  
Multidrug Resistant ◽  
The Novel ◽  
Mice Model ◽  
P Glycoprotein ◽  
Channel Currents

MDR (multidrug-resistance) represents a major obstacle to successful cancer chemotherapy and is usually accomplished by overexpression of P-gp (P-glycoprotein). Much effort has been devoted to developing P-gp inhibitors to modulate MDR. However, none of the inhibitors on the market have been successful. 1416 [1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (phenoprolamine hydrochloride)] is a new VER (verapamil) analogue with a higher IC50 for blocking calcium channel currents than VER. In the present paper, we examined the inhibition effect of 1416 on P-gp both in vitro and in vivo. 1416 significantly enhanced cytotoxicity of VBL (vinblastine) in P-gp-overexpressed human multidrug-resistant K562/ADM (adriamycin) and KBV cells, but had no such effect on the parent K562 and KB cells. The MDR-modulating function of 1416 was further confirmed by increasing intracellular Rh123 (rhodanmine123) content in MDR cells. Human K562/ADM xenograft-nude mice model verified that 1416 potentiates the antitumour activity of VBL in vivo. RT-PCR (reverse transcriptase-PCR) and FACS analysis demonstrated that the expression of MDR1/P-gp was not affected by 1416 treatment. All these observations suggest that 1416 could be a promising agent for overcoming MDR in cancer chemotherapy.

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