Continuous administration of endostatin by intraperitoneally implanted osmotic pump improves the efficacy and potency of therapy in a mouse xenografttumor model

In the first Phase I clinical trials of endostatin as an antiangiogenic the rapy for cancer, the protein was administered as an i.v. bolus for similar to 20-30 min each day. This protocol was based on experimental studies in w hich animals were treated by s.c. bolus once a day. However, it was not cle ar in the previous studies whether this schedule could be maximized further . Therefore, we developed experimental models involving continuous administ ration 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 endost atin administered continuously via an i.p. implanted mini-osmotic pump. Our results show that endostatin remains stable and active in mini-osmotic pum ps for at least 7 days. We show that endostatin injected i.p. is rapidly cl eared within 2 h, whereas endostatin administered continuously via mini-osm otic pump maintains systemic concentrations of 200-300 ng/ml for the durati on of administration. Furthermore, continuous i.p. administration of endost atin results in more effective tumor suppression at significantly reduced d oses (5-fold), compared with bolus administration. Additional experiments u sing a human pancreatic cancer model in severe combined immunodeficient mic e showed that there was a significant decrease in the microvessel density b etween the treatment groups and the control group. These data show that con tinuous administration of human endostatin results in sustained systemic co ncentrations of the protein leading to: (a) increased efficacy manifested a s increased tumor regression; and (b) an 8-10-fold decrease in the dose req uired to achieve the same antitumor effect as the single daily bolus admini stration of endostatin. On the basis of this approach, an additional clinic al trial has been designed and initiated and is under way in two countries.