However, chemotherapy in megadose is followed by serious side effects such as nausea, vomiting, hair loss, neurotoxicity and myelosuppression. In general, the responses GSK1210151A in patients are unabiding with relapses accompanied by acquired resistance to the cytotoxic drugs in some heterogeneous survival cells because of indirect selection of chemotherapeutic drugs. At present the conventional dosing schedule is applied to balance the toxicity and efficacy, but the severe
side effects and the ultimate failures remain refractory obstacles to administration of most chemotherapies. So new approaches are required to achieve a high therapeutic response rate. A conventional dosing chemotherapy calls ACP-196 concentration for episodic application of a cytotoxic drug, and requires a period of rest during chemotherapy to let normal cells recover. With a low rate of replication and cell division (the proliferation index of endothelial cells in tumor vessels is usually less than 3%), the tumor-associated endothelial cells are only weakly damaged in the standard chemotherapy. Tumor-related angiogenesis can supply essential nutrients and oxygen for the remaining tumor cells,
which makes tumor relapse possible. Our current research confirmed that this website intratumoral injection of recombinant endostatin adenovirus plus a low dose of cisplatin could evidently improve antitumor efficacy, including tumor growth suppression, mice survival prolongation, and tumor cell apoptosis augmentation as well as neovascularization inhibition as compared with the controls. No serious adverse effects, such as ruffled fur, cachexia, anorexia, behavior change or toxic death were found in the combination group. However, up to now, the exact mechanism is not clear that how the combined agents induced anti-tumor
efficacy. Two possible mechanisms may get involved. The first is induction of apoptosis. The antiangiogenic agents decrease supply of oxygen and nutrients for the tumor cells by reducing tumor vascular density, perfusion and vascular permeability, which leads to apoptosis Sucrase of tumor cells and thus reinforces apoptosis efficacy of cisplatin. However, it is not clear whether the function of cisplatin in tumors is independent on gene transfer or is a specific part of adenovirus gene transfer. The second is antiangiogenesis. Cisplatin has been reported to influence the process of vascularization and to cause severe vasculotoxicity, which can strengthen the antiangiogenesis efficacy of endostatin. Low-dose cytotoxic treatment and antiangiogenesis therapy interact on each other. If the endothelial cells are treated by antiangiogenesis agents, they will lack certain adhesive contacts with matrix. Nonadherent endothelial cells are more susceptible to a cytotoxic agent, resulting in a higher apoptosis rate.