Also, future research will be necessary to answer other questions.A fourth compartment can be considered as the concentration of endostatin in and around angiogenic vessels in tumors, and possibly at other angiogenic sites.Pretreatment with endostatin blocks the permeability induced by these proteins. These results imply that systemic administration of endostatin to patients may decrease edema in brain tumors, but this speculation has not yet been tested.Wounding the tumor site or moving the tumor to another site in the same mouse initiated tumor neovascularization and growth.Another possibility is preferential storage of endostatin in the matrix at the site of the regressed tumor.We have observed this same dormancy after days of endostatin therapy of rat mammary cancer induced by an oral carcinogen.Soluble recombinant endostatin A wide variety of other tumors in many different laboratories have been Glimepiride inhibited by endostatin in mice and rats without evidence of toxicity or drug resistance.Inhibition of tumor growth persisted after cessation of therapy.This stimulus needs to be continuously opposed by inhibitors in the blood.An analogy would be titration of blood glucose by insulin, where endothelium is glucose.In a compelling experiment, hour continuous parenteral administration of human endostatin was fold more effective than the same dose administered as a bolus once every day, against human pancreatic cancer in SCID immunodef icient mice. Tumorgrowth was inhibited in a dosedependent manner, but only continuous administration caused tumor reg ression.It should be noted that continuous administration of endostatin in vitro inhibited endothelial proliferation more signif icantly than once daily addition of endostatin.Tumors underwent regression when treated with a combination of ionizing radiation and endostatin, but not with either agent alone, even when the endostatin dose was lowered below the effective dose and the tumor cells were radioresistant.It can be speculated that radiation damage to active endothelium in a tumor bed may not be repaired in the presence of an angiogenesis inhibitor.This experiment also suggests that radiotherapy may be in part endothelialdependent.Mice treated with the combination were protected against subsequent tumor challenge with unmodif ied cells.Endostatin also potentiates conventional chemotherapy in tumorbearing animals.However, it is not clear how combinations of antiangiogenic therapy and chemotherapy at maximum tolerated dose schedules will translate to patients. After days, control tumors reached mm compared to mm for endostatin transduced tumor cells. Examples are inhibition of human liver carcinoma, renal cell carcinoma, mouse melanoma.Of interest is that intratumoral gene transfer of endostatin inhibited mouse mammary tumors, but had a minimal effect in human breast MDAMD in SCID mice.Despite many successes of endostatin gene transfer into tumor cells, unsolved Icariin problems remain.The fact that one author can report marked and sustained tumor inhibition with endostatin transduction of a mouse breast cancer, but minimal effect in a human breast cancer MDAMD, highlights the problem.A third author reports marked inhibition by endostatin gene transfer into a human breast cancer MDAMBA, but minimal effect in MCF, yet angiostatin gene transfer into MCF was very inhibitory, but had only minimal effect on MDAMB breast cancer cells.For unknown reasons, the inhibitor may lose activity when produced by one type of tumor cell, but not by another.