BCNU Combined With VEGF Antibody For The Treatment Of Malignant Glioma

Glioma is a kind of malignant tumor in central nervoussystem, which has a high disease rate. The rate is about35.26-60.96 percent of all kinds of nervous system tumor and44.69% in average. For malignant glioma, there hasn't a perfecttherapy to cure, but we major on the operation to remove the tumor,and assist with radiotherapy, chemotherapy, immunotherapy andgene therapy i. e. after operation. Still, operation is preferred, Butoperation can't completely remove the whole glioma, and mostglioma will recur after operation, for the invading growing styleand non-clear borderline of the tumor. We are still working on anew way to accomplish this task.Even though many scholar andneurosurgeons try their best to find a unified, normative therapy,all of them have failed. Chemotherapy is one of three major strategy of tumor cure,but there are a lot of inconveniences for this method. The effect ofdrugs depends on dose mostly, that is to say, chemotherapy canwork in vivo only when certain blood concentration is reached. Butwhen the blood concentration is beyond a higher line, side effectswill display. So the range of cure dose is limited. In addition, dueto the existing of hematoencephalic barrier and multidrugresistance, there still are tumor cells remained after chemo. So,theideal chemotherapeutics shoud have three conditions: 1. Beingeasy to pass the hematoencephalic barrier. 2. There is no adversereaction. 3. There is no drug resistance after long term application。Unfortunately,no ideal chemotherapeutics like that appears atpresent.Now it is admitted that the most effectivechemotherapeutics is carmustine (BCNU).As the choice drug in glioma chemo, BCNU has a highliposolubility and is easy to pass the hematoencephalic barrier.It cansuppress the copy and expression of DNA, there are effects in everystage of cell proliferation. But the overdose of BCNU can inducebone marrow depression, the functional lesion of live and kidney,pulmonary fibrosis, phlebitis etal, so in the course of chemo, thedose of BCNU is limited strictly. The effect of BCNU must bedepressed in the wake of dose limitation. For the purpose ofimproving the prognosis of the patient, we should combine otherstrategy with the traditional operation+radiotherapy+chemotherapy.VEGF derived from the cancinoma is the center factor in theangiogenesis. The production of the VEGF is regulated by growthfactor, cell factor, and other factors, which can not directlycontribute to the angiogenesis, but via the secretion of VEGF.VEGF alternatively directly act on two kinds of Tyrosine Kinasesreceptor on the surface of vessel endothelial cells, which whenbinding to VEGF can induce self-phosphorylation and the signaltransmitting in vessel endothelial cells, promote the proliferation ofvessel endothelial cell, and eventually increase the blood stream ofthe carcinoma, which leads to the hyperplasia. Via interrupting thebinding of VEGF and its acceptor, VEGF antibody depresses theangiogenesis of glioma and Inhibit its malignant growth。Our study is major on the further research of cooperationbetween BCNU and VEGF antibody.Objective:To investigate the inhibitory effect of the C6 glioma's growthand proliferation by combining BCNU with VEGF antibodythrough animal experiment.Method:1. we establish the subcutaneous model of rat C6 glioma.2. we classify all these models randomly into 4groups (namedⅠ , Ⅱ , Ⅲ , Ⅳ), each had 8 rats, which were bred separately.The ratsin group I are administrated Physiological saline;the rats in groupⅡ are administrated VEGF antibody;the rats in group Ⅲ areadministrated BCNU, the rats in group Ⅳ are administrated VEGFantibody and BCNU.3. After 2 weeks, we kill all the rats, dissect the gliomaspecimen.and weigh, then calculate the suppression ratio.4. we survey and evaluate MVD and the positive rate of C-mycprotein's expression in every group by immunohistochemistry.Result1. suppression ratio: The suppression ratio of group Ⅱ , Ⅲ , Ⅳis separately 28.11±7.80%, 46.80±3.01% and 62.18±4.86%. Thesuppression ratio of group Ⅲ is higher apparently than the one ofgroup Ⅱ(P<0.01);The suppression ratio of groupⅣ is higherapparently than the one of group Ⅲ (P<0.01).2. MVD: The MVD of groupⅠ , Ⅱ , Ⅲ , Ⅳ is separately 24.24±2.88, 14.63±0.86, 14.20±0.45, 7.55±0.58. The MVD of groupⅡand group Ⅲ are both lower than group Ⅰ (P<0.01), The MVD ofgroup Ⅳ is apparently lower than group Ⅱ , Ⅲ Ⅰ (P<0.01). There isno obviously difference between the MVD of group Ⅱ and the oneof group Ⅲ (P>0.05).3. the positive rate of C-myc protein's expression: the positiverate of C-myc protein's expression of group Ⅰ , Ⅱ , Ⅲ , Ⅳ isseparately 80.99±6.04%, 61.50±5.81%, 40.35±3.02%, 13.00±4.07%.There are obviously difference between them (P<0.01).ConclusionCompared to control group, BCNU and VEGF antibody allhave the proliferation inhibitory effect of C6 glioma measured inweight, MVD and the positive rate of C-myc protein's expression.While combined with VEGF multiclone antibody, BCNU canprovide a more strength effect in antitumor therapy.