Enhancement of ricin A chain immunotoxin activity by perhexiline on established and fresh leukemic cells.
In the perspective of increasing the clinical potential of ricin A chain immunotoxins (RTA-ITs), perhexiline (Pex) and four structural analogues (Pex 2, Pex 3, Pex 7, and Pex 11) were evaluated for their ability to enhance RTA-IT activity in vitro. Only perhexiline significantly enhanced the cytotoxic activity of anti-CD5 RTA-ITs, T101 and T101-F(ab')2, on CEM III cell line (30- to 2000-fold), and of anti-HLA-DR RTA-IT, HNC-241, on both RAJI cell line (greater than 100-fold) and two immortalized cell lines originating from patients suffering from B-cell chronic lymphocytic leukemia, EHEB and FS2 D5 (10-fold). On 16 consecutive fresh B-cell chronic lymphocytic leukemia cell samples, significant T101-F(ab')2 RTA-IT and HNC-241 RTA-IT enhancement was observed with perhexiline which was comparable to that of NH4Cl and monensin. Perhexiline almost completely blocked RTA-IT intracellular degradation and profoundly modified its routing. These observations were linked to perhexiline-induced lipidosis via inhibition of sphingomyelinase activity. In conclusion, since the concentrations used are relevant with the pharmacokinetics of this agent, perhexiline appears to be a promising agent for in vivo enhancement of ricin A chain immunotoxins.
Jaffrézou
J P
JP
Laboratoire de Pharmacologie et de Toxicologie Fondamentales, CNRS, Toulouse, France.
Levade
T
T
Kuhlein
E
E
Thurneyssen
O
O
Chiron
M
M
Grandjean
H
H
Carrière
D
D
Laurent
G
G
D000643:Ammonium Chloride / Q000494:pharmacology; D000911:Antibodies, Monoclonal; D002460:Cell Line; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D007700:Kinetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000473:pathology*; D008985:Monensin / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010480:Perhexiline / Q000031:analogs & derivatives / Q000494:pharmacology*; D012276:Ricin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D014700:Verapamil / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D009363:Neoplasm Proteins; D000643:Ammonium Chloride; D012276:Ricin; D008985:Monensin; D014700:Verapamil; D010480:Perhexiline