The cyclosporin PSC 833 prolongs survival of NOD-SCID mice following xenotransplantation with human myeloblasts carrying P-glycoprotein

G Lehne MD PhD a, D Sørensen DVM MSc b, GE Tjønnfjord MD PhD c, C Beiske MD PhD d, HE Rugstad MD PhD a, T-A Hagve MD PhD e, OPF Clausen MD PhD d

Department of Clinical Pharmacology a, Department of Comparative Medicine b, Department of Internal Medicine c, Institute for Pathology d, and Department of Clinical Chemistry e, Rikshospitalet University Hospital, N-0027 Oslo, Norway

AIM. The multidrug transporter P-glycoprotein (Pgp), which frequently appears in the plasma membrane of multiresistant cancer cells, is a membrane efflux pump for endogenous substances such as certain cytokines and sphingolipids. Accordingly, Pgp may act as a primary antiapoptotic molecule, and Pgp-selective modulators may separately inhibit cell growth and induce apoptosis in multiresistant leukemia cells in vitro (G Lehne et al., Leukemia, 1999; 13: 768-778). In the present study we addressed the consequence of Pgp blockade in vivo using the cyclosporin PSC 833 as modulator in a xenotransplant model of KG1a/200 human myeloblastic leukemia. METHODS. Initially, 107 exponentially growing KG1a/200 cells were injected into the tail vein of non-obese diabetic severe combined immunodeficient (NOD-SCID) mice. The animals were randomly allocated to receive treatment with PSC 833 (N = 32) or placebo (N = 24). PSC 833 (30 mg/kg) was subcutanously injected 6 or 12 times separated by 48-96 hours. The study animals were closely monitored by daily inspection, bi-weekly weighing, and blood analyses every second week for up to 92 days. Criteria for extermination were weight-loss ³ 20%, incapacitating macroscopic tumors, or debilitating illness according to institutional guidelines. RESULTS . Pgp was highly expressed in the KG1a/200 cells. The overall mean whole blood concentration of PSC 833 was 1191 ± 60 ng/ml (SEM) at 20 hours after administration. Tumor engraftment was reduced form 42% in the placebo group to 16% in the treatment group (P = 0.037), and overall survival was significantly prolonged in animals that were treated with PSC 833 (P = 0.0016). CONCLUSIONS. This is the first study that demonstrates antileukemic effects of a Pgp inhibitor as single agent therapy in vivo, and the present data rises a possibility for alternative exploitation of modulators in cancer chemotherapy.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Multidrug Resistance - MDR.