The cyclosporin PSC 833 increases survival and delays engraftment of human multidrug-resistant leukemia cells in xenotransplanted NOD-SCID mice.
Circumvention of chemoresistance in cancer may involve several modulator drugs with high affinity for the multidrug transporter P-glycoprotein (Pgp), which is expressed in a number of multi-resistant malignancies. Pgp acts as a membrane efflux pump with broad substrate specificity including antineoplastic drugs and endogenous substances such as certain cytokines and sphingolipids. Therefore, the consequence of Pgp blockade could be far more complex than intracellular drug retention. In the present study exposure of the Pgp inhibitor, PSC 833 (1200 ng/ml), to Pgp expressing KG1a/200 human leukemia cells provoked cell cycle arrest and apoptosis in vitro. This finding was put to test in vivo using a xenotransplant model of KG1a/200 human cells intravenously inoculated into 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 subcutaneously injected six or 12 times separated by 48-96 h. The overall mean whole blood concentration of PSC 833 was 1191 +/- 60 ng/ml (s.e.m.) at 20 h after administration. Tumor engraftment was significantly reduced in the treatment group (P = 0.037), which also had prolonged survival compared to control animals (P = 0.0016). This is the first study that demonstrates antileukemic effects of a Pgp inhibitor as single agent therapy in vivo, and the present data raise the possibility of alternative exploitation of modulators in cancer chemotherapy.
Lehne
G
G
Department of Clinical Pharmacology, Rikshospitalet University Hospital, Oslo, Norway.
Sørensen
D R
DR
Tjønnfjord
G E
GE
Beiske
C
C
Hagve
T-A
TA
Rugstad
H E
HE
Clausen
O P F
OP
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003524:Cyclosporins / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015996:Survival Rate; D014183:Transplantation, Heterologous
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; C070272:valspodar