Immunotoxin treatment targeted to the high-molecular-weight melanoma-associated antigen prolonging the survival of immunodeficient rats with invasive intracranial human glioblastoma multiforme.
OBJECTIVE
The aim of this study was to target immunotoxin treatment to the high-molecular-weight melanoma-associated antigen (HMW-MAA) and thereby examine any changes in the survival of immunodeficient rats with human glioblastoma multiforme (GBM).


METHODS
To target treatment specifically to human glioma cells, Pseudomonas exotoxin A (PE) was conjugated to the 9.2.27 antibody, which recognizes the HMW-MAA. Treatment of the antigen-positive glioma cell line U87MG with the resulting 9.2.27-PE caused cytotoxicity with a median inhibitory concentration of 1 ng/ml. Intratumoral 9.2.27-PE treatment of intracranial U87MG tumors in nude rats prolonged the survival of these animals by 43% compared with controls. In additional studies on the use of this targeted treatment, the authors precultured freshly dissected glioblastoma multiforme (GBM) biopsy tissue for 1 to 2 weeks. Inoculation of this tissue into the rat brain resulted in diffuse infiltrative gliomas. The markers glial fibrillary acidic protein and S100 protein were found to be expressed in the original biopsy specimens, as well as in the glioma xenografts in nude rat brains. Intratumoral immunotoxin treatment of such established tumors with 9.2.27-PE was effective and prolonged survival time from 30% to as high as 90% in animals with tumors originating from four different GBM specimens.


CONCLUSIONS
Targeted treatment of highly invasive GBMs proved effective, and these results emphasize the clinical relevance of this antigen as a target molecule for immunotoxin treatment of human GBMs.
Hjortland
Geir Olav
GO
Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, Oslo, Norway. g.o.hjortland@labmed.uio.no
Garman-Vik
Solveig Suzanne
SS
Juell
Siri
S
Olsen
Oyvind Edon
OE
Hirschberg
Henry
H
Fodstad
Oystein
O
Engebraaten
Olav
O
D036002:ADP Ribose Transferases / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm / Q000276:immunology*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001427:Bacterial Toxins / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000276:immunology; D045744:Cell Line, Tumor; D005098:Exotoxins / Q000627:therapeutic use*; D005909:Glioblastoma / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D023421:Models, Animal; D009368:Neoplasm Transplantation; D051381:Rats; D011923:Rats, Nude; D016019:Survival Analysis; D037521:Virulence Factors / Q000627:therapeutic use*; D000097668:Pseudomonas aeruginosa Exotoxin A; D000099216:Chondroitin Sulfate Proteoglycan 4
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D005098:Exotoxins; D000922:Immunotoxins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; D000099216:Chondroitin Sulfate Proteoglycan 4