c-erbB-2/p185-directed therapy in human lung adenocarcinoma.
BACKGROUND
These experiments were conducted to determine whether p185 can be therapeutically targeted in adenocarcinoma of the lung using an anti-p185-gelonin conjugate. c-erbB-2/p185 is overexpressed in up to one third of non-small cell lung cancers. CALU-3 is a human lung adenocarcinoma cell line that overexpresses p185. muMoAb-4D5 is a murine anti-p185 monoclonal immunoglobulin G1. Gelonin is a potent type 1 ribosomal inhibitory protein.


METHODS
4D5 and gelonin were covalently modified and linked. Purification was confirmed by SDS-polyacrylamide gel electrophoresis. Dose-dependent cytotoxicity was quantified using 3H-thymidine uptake by CALU-3 cells after incubation with 4D5-gelonin conjugate or with control substances (4D5, gelonin, unconjugated 4D5 + gelonin, or control antibody MOPC-21).


RESULTS
The 4D5-gelonin conjugate showed a 50% inhibitory concentration of 3.5 x 10(-10) mol/L, but 4D5 alone demonstrated no cytotoxic effect. Gelonin and the unconjugated 4D5-gelonin mixture had one tenth the cytotoxicity of the 4D5-gelonin conjugate (inhibitory concentration = 6.5 x 10(-9) mol/L and 8.5 x 10(-9) mol/L, respectively). The conjugate exhibited minimal toxicity against a p185-negative cell line (NIH3T3).


CONCLUSIONS
Selective and efficient killing of human lung adenocarcinoma cells can be achieved in vitro using c-erbB-2/p185-directed therapy.
Snider
J M
JM
Division of Cardiothoracic Surgery, University of Iowa Hospitals and Clinics, Iowa City, USA.
Bushnell
L J
LJ
Chen
L C
LC
Lanza
L A
LA
D000230:Adenocarcinoma / Q000188:drug therapy*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004273:DNA, Neoplasm / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D008175:Lung Neoplasms / Q000188:drug therapy*; D010940:Plant Proteins / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D054789:Ribosome Inactivating Proteins, Type 1; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D007074:Immunoglobulin G; D010940:Plant Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D054789:Ribosome Inactivating Proteins, Type 1; C025674:GEL protein, Gelonium multiflorum