Continuous administration of endostatin by intraperitoneally implanted osmotic pump improves the efficacy and potency of therapy in a mouse xenograft tumor model.
In the first Phase I clinical trials of endostatin as an antiangiogenic therapy for cancer, the protein was administered as an i.v. bolus for approximately 20-30 min each day. This protocol was based on experimental studies in which animals were treated by s.c. bolus once a day. However, it was not clear in the previous studies whether this schedule could be maximized further. Therefore, we developed experimental models involving continuous administration of endostatin to determine the potency and efficacy of this approach. Endostatin was administered to tumor-bearing mice either s.c. or i.p. in single bolus doses. The efficacy of these regimens was compared with endostatin administered continuously via an i.p. implanted mini-osmotic pump. Our results show that endostatin remains stable and active in mini-osmotic pumps for at least 7 days. We show that endostatin injected i.p. is rapidly cleared within 2 h, whereas endostatin administered continuously via mini-osmotic pump maintains systemic concentrations of 200-300 ng/ml for the duration of administration. Furthermore, continuous i.p. administration of endostatin results in more effective tumor suppression at significantly reduced doses (5-fold), compared with bolus administration. Additional experiments using a human pancreatic cancer model in severe combined immunodeficient mice showed that there was a significant decrease in the microvessel density between the treatment groups and the control group. These data show that continuous administration of human endostatin results in sustained systemic concentrations of the protein leading to: (a) increased efficacy manifested as increased tumor regression; and (b) an 8-10-fold decrease in the dose required to achieve the same antitumor effect as the single daily bolus administration of endostatin. On the basis of this approach, an additional clinical trial has been designed and initiated and is under way in two countries.
Kisker
O
O
Division of Surgical Research, Children's Hospital, Boston, Massachusetts 02115, USA.
Becker
C M
CM
Prox
D
D
Fannon
M
M
D'Amato
R
R
Flynn
E
E
Fogler
W E
WE
Sim
B K
BK
Allred
E N
EN
Pirie-Shepherd
S R
SR
Folkman
J
J
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy; D003094:Collagen / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004355:Drug Stability; D043169:Endostatins; D005354:Fibrosarcoma / Q000098:blood supply / Q000188:drug therapy; D006801:Humans; D015918:Infusion Pumps, Implantable; D007263:Infusions, Parenteral; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009997:Osmotic Pressure; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D043169:Endostatins; D010446:Peptide Fragments; D003094:Collagen