Reversal of Vinca alkaloid resistance by anti-P-glycoprotein monoclonal antibody HYB-241 in a human tumor xenograft.
A panel of monoclonal antibodies (MAbs) to P-glycoprotein was developed by immunization of mice with multidrug-resistant human neuroepithelioma and neuroblastoma cells. All the anti-P-glycoprotein MAbs reacted with the extracellular portion of P-glycoprotein. The MAbs were examined for their ability to enhance accumulation of actinomycin D, vincristine, vinblastine, and doxorubicin in the human mdr1 transfectant cell line, BRO/pFRmdr1.6. HYB-241, an IgG1 anti-P-glycoprotein MAb, was the most effective modulator, increasing actinomycin D levels in the transfectant line by 6-fold, vincristine by 2-fold, and vinblastine levels by 3-fold. None of the MAbs were capable of modifying the accumulation of doxorubicin. HYB-241 lowered the 50% inhibitory concentration values of actinomycin D by 11-fold, vincristine by 6-fold, and vinblastine by 2-fold. No effect on the 50% inhibitory concentration values of doxorubicin or gramicidin were seen. 111In-labeled HYB-241 localized in human tumor xenografts of BRO/pFRmdr1.6 in nude mice (25% injected dose/g at 120 h). Mice with established drug-resistant xenografts were treated with antibody 24 h prior to the injection of Vinca alkaloid at concentrations known to be non-growth inhibitory. The addition of HYB-241 at 25 mg/kg per injection prior to drug resulted in a significant inhibition of growth of this drug-resistant tumor.
Hybritech Incorporated, San Diego, California 92121.
L S
LS
Rittmann-Grauer
M A
MA
Yong
V
V
Sanders
D G
DG
Mackensen
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000911:Antibodies, Monoclonal / Q000302:isolation & purification / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003609:Dactinomycin / Q000378:metabolism / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics / Q000502:physiology*; D005260:Female; D006801:Humans; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C / Q000276:immunology; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000188:drug therapy / Q000628:therapy*; D018241:Neuroectodermal Tumors, Primitive, Peripheral / Q000188:drug therapy / Q000628:therapy*; D014162:Transfection; D014183:Transplantation, Heterologous; D014747:Vinblastine / Q000378:metabolism / Q000627:therapeutic use*; D014750:Vincristine / Q000378:metabolism / Q000627:therapeutic use*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; D003609:Dactinomycin; D014750:Vincristine; D014747:Vinblastine