Listeriolysin O potentiates immunotoxin and bleomycin cytotoxicity.
Antitumor immunotoxins were formed by covalently attaching the ribosome-inactivating protein ricin A chain (RA) to the antitumor antibodies BR96 and L6. In vitro cytotoxicity assays established that BR96-RA was cytotoxic to H2987 human lung adenocarcinoma cells (IC50 = 6 nM), while L6-RA exhibited very low levels of cytotoxic activity (18% cell kill at 67 nM). The virulence factor from the intracellular pathogen Listeria monocytogenes, listeriolysin O (LLO), was able to potentiate the cytotoxicity of BR96-RA and L6-RA by 120- and > 1340-fold, respectively, resulting in IC50 values of approximately 50 pM. LLO also potentiated the cytotoxicity of the peptide anticancer drug bleomycin by a factor of > 2500 but had no effect on the cytotoxic activities of the anticancer drugs cytarabine and etoposide phosphate. In addition, LLO did not potentiate the cytotoxic activity of unconjugated ricin A chain or L6-RA on H2987 cells that were saturated with L6 prior to conjugate treatment. These results are attributed to LLO-induced alteration of the intracellular trafficking of molecules that are incorporated into acidic vesicles.
Kerr
D E
DE
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA.
Wu
G Y
GY
Wu
C H
CH
Senter
P D
PD
D000230:Adenocarcinoma / Q000188:drug therapy*; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000008:administration & dosage; D001427:Bacterial Toxins; D001761:Bleomycin / Q000008:administration & dosage; D004357:Drug Synergism; D006360:Heat-Shock Proteins / Q000008:administration & dosage; D006460:Hemolysin Proteins / Q000008:administration & dosage; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy*; D012276:Ricin / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D000922:Immunotoxins; D001761:Bleomycin; D012276:Ricin; C038705:hlyA protein, Listeria monocytogenes