Radioimmunotherapy of solid tumors targeting a cell-surface protein, FZD10: therapeutic efficacy largely depends on radiosensitivity.
OBJECTIVE
Frizzled homolog 10 (FZD10) is expressed at high levels on the cell surface of almost all synovial sarcoma tissues, but is absent in most normal organs. In a previous study, yttrium-90 ((90)Y)-labeled anti-FZD10 antibody (MAb 92-13) showed considerable therapeutic efficacy in synovial sarcoma cell-bearing mice. The purpose of the present study was to elucidate the factors associated with this therapeutic efficacy of (90)Y-MAb 92-13.


METHODS
FZD10 expression levels of SYO-1 (FZD10-overexpressing synovial sarcoma cell line) and DLD-1/FZD10 (FZD10-transfected DLD-1 cell) were determined by the cell binding assay, and their radiosensitivity was evaluated by incubation with (90)Y-MAb 92-13 in vitro. Biodistribution study of indium-111 ((111)In)-MAb 92-13 was performed in SYO-1 and DLD-1/FZD10 tumor-bearing mice. For therapeutic studies, SYO-1 and DLD-1/FZD10 tumor-bearing mice were treated with (90)Y-MAb 92-13 (100, 150, and 200 muCi), after which the change in tumor volume was measured. Immunohistochemical staining was performed on the excised tumor.


RESULTS
Expression level of FZD10 on DLD-1/FZD10 was much greater than that on SYO-1. The accumulation of (111)In-MAb 92-13 was much higher in DLD-1/FZD10 tumor-bearing mice than in SYO-1 tumor-bearing mice (49.0 +/- 4.2 and 22.0 +/- 4.5% ID/g, respectively, at 48 h after administration). In SYO-1 tumor, substantial tumor size reduction was observed in all mice treated with (90)Y-MAb 92-13 (tumor volume decreased to less than 0.1 cm(3) at 11 days after treatment) and tumor regrowth was not observed in most of them. In contrast, only slow progression was observed in DLD-1/FZD10 tumor. When incubated with (90)Y-MAb 92-13, high radioactivity was needed to damage DLD-1/FZD10. Immunohistochemical study indicated apoptosis of SYO-1 tumor.


CONCLUSIONS
The therapeutic efficacy of RIT seems to largely depend on the tumor radiosensitivity.
Department of Bioimaging Information Analysis, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Japan. hhanaoka@med.gunma-u.ac.jp
Hirofumi
H
Hanaoka
Toyomasa
T
Katagiri
Chikako
C
Fukukawa
Hiroki
H
Yoshioka
Shinji
S
Yamamoto
Yasuhiko
Y
Iida
Tetsuya
T
Higuchi
Noboru
N
Oriuchi
Bishnuhari
B
Paudyal
Pramila
P
Paudyal
Yusuke
Y
Nakamura
Keigo
K
Endo
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D001692:Biological Transport; D045744:Cell Line, Tumor; D002470:Cell Survival; D051157:Frizzled Receptors / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy* / Q000628:therapy; D011836:Radiation Tolerance; D016499:Radioimmunotherapy; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D014018:Tissue Distribution; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; C121168:FZD10 protein, human; D051157:Frizzled Receptors; D043562:Receptors, G-Protein-Coupled