Continuous versus intermittent administration of human endostatin in xenografted human neuroblastoma.
OBJECTIVE
The authors examined whether recombinant human endostatin (rhEndostatin), an antiangiogenic agent, is effective against a human neuroblastoma cell line (designated TNB9) using a human neuroblastoma xenograft model and investigated whether continuous infusion is more effective than intermittent administration.


METHODS
In the first experiment, when tumors on the back of nude mice reached a weight of 90 to 95 mg, rhEndostatin, 10 mg/kg/d mouse weight, was administered subcutaneously to the mice (n = 5) every day for 10 consecutive days. In the second experiment, the same daily dose of rhEndostatin was administered continuously to the TNB9-bearing mice (n = 6) via subcutaneous infusion pumps for 3 consecutive days with total dose being 30% of that in the first experiment. Nestin and factor VIII expression levels were studied immunohistochemically to elucidate whether histologic evidence of the effects of rhEndostatin was present on day 4 in the second experiment.


RESULTS
In the first experiment, relative tumor weight in treated mice (n = 5) was significantly less than that in controls (n = 12) on day 2 only after treatment initiation (P <.05). The maximum inhibition rate (MIR) of TNB9 xenograft growth by rhEndostatin was 46.4%, indicating lack of efficacy. In the second experiment, the effects of rhEndostatin were much more marked than those in the first experiment, with an MIR of 60.7%. The mean relative tumor weight in the treated group (n = 6) in the second experiment was significantly less than that in controls (n = 10) on days 2, 4, and 6 (P <.01) as well as on days 8 and 10 (P <.05). Nestin staining in the endothelium of control tumors (n = 2) was marked, whereas it showed a loss of fibrillar structure in rhEndostatin-treated tumors (n = 2). The number of vessels immunostained with antifactor VIII antibody was markedly reduced in tumors (n = 2) from rhEndostatin-treated mice compared with that in tumors from control animals (n = 2).


CONCLUSIONS
Continuous administration of rhEndostatin resulted in more significant tumor regression than intermittent administration of the agent in the same model. This indicates that rhEndostatin, if administered in continuous fashion, could become an effective agent for treating patients with neuroblastoma in the future.
Kuroiwa
Minoru
M
Department of Surgery, Gunma Children's Medical Center, Gunma, Japan.
Takeuchi
Toshiyuki
T
Lee
Jung Hee
JH
Yoshizawa
Jyoji
J
Hirato
Junko
J
Kaneko
Setsuko
S
Choi
Seung Hoon
SH
Suzuki
Norio
N
Ikeda
Hitoshi
H
Tsuchida
Yoshiaki
Y
D000008:Abdominal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D043169:Endostatins / Q000008:administration & dosage*; D005169:Factor VIII / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015918:Infusion Pumps, Implantable; D007279:Injections, Subcutaneous; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D011994:Recombinant Proteins; D012074:Remission Induction; D023041:Xenograft Model Antitumor Assays
D043169:Endostatins; D011994:Recombinant Proteins; D005169:Factor VIII