| MIG (monokine induced by IFN-γ), is a member of CXC chemokines. CXC chemokines are characteristically heparin-binding proteins. On a structural level, they have four highly conserved cysteine amino acid residues, with the first two cysteines separated by one nonconserved amino acid residue. Although the CXC motif distinguishes this family from other chemokine families, a second structural domain dictates their angiogenic activity. The NH2 terminus of the majority of the CXC chemokines contain a three-amino-acid motif (Glu-Leu-Arg: the ELR motif), which precedes the first cysteine amino acid of the primary structure of these cytokines. The family members that contain the ELR motif (ELR+) mainly include interleukin-8 (IL-8), growth-related genes (GRO-α,β,γ), granulocyte chemotactic protein-2 (GCP-2), which are potent promoters of angiogenesis and neutrophil chemotaxis, inducing inflammation. In contrast, the members of CXC chemokines which lack the characteristic proangiogenic ELR motif (ELR-) are potent inhibitors of angiogenisis, which mainly includeCXCL9/MIG, CXCL10/IP-10 and PF-4. The CXCR3 serves as the receptor for MIG and IP-10, which is expressed exclusively on T and NK cells after activation by IFN- y, MIG also functions in vivo as a potent chemoattractant for tumor-infiltrating lymphocytes, activated peripheral blood lymphocytes, as well as NK cells and THi lymphocytes. So MIG is a potential candidate for anti-angiogenic and immunornodulation therapy for tumor. In recent years, several new chemotherapy regimes are emerged, including frequently protract administration of low dosages of conventional chemotherapeutic drugs at a metronomic schedule. They are less toxic, damage or kill the endothelial cells of tumor neovasculature, and delay acquired resistance to chemotherapeutic drugs. Another advantage of metronomic chemotherapy is the possibility of combining it with anti-angiogenic drugs, as well as other types of targeted therapies — such those that target specific signal-transduction molecules — or with antitumour vaccines and gene therapy.A combined treatment strategy was designed using pOKF-MIG gene therapy plus low-dose cisplatin chemotherapy to determine the antitumor ability. And the antitumor activity of the combined program was evaluated in two immunocompetent mice loaded with Lewis lung carcinomas (LL/2) and Colon carcinomas (CT26). The treatment protocols were designed by administering pORF-M/G intramuscularly at 100p.g / mouse twice a week for 4 weeks, and / or cisplatin intraperitoneally at 0.6 mg / kg / mouse every 3 days for 42 days. Tumor volume and survival time were observed. CD31 immunohistochemistry staining of tumor tissues and alginate capsule models in vivo were used to evaluate angiogenesis. Assessment of apoptotic cells in tumor tissues and CTL activities of lymphocytes were also conducted. Thecombined treatment improved antitumor activity with completed tumor regression in 3/10 of LL/2c lung carcinaomas, 4/10 of CT26 colon carcinaomas and significantly prolonged the life span of tumor bearing mice compared with the control. The synergistic anti-angiogenesis activity, augmented induction of apoptosis and elevated CTL activities were observed in the combined treatment group. These studies provided the basis for further clinical development in the treatment of solid tumors by combination of the anti-angiogenic gene therapy with metronomic delivery of conventional anti-neoplastic agents.
|
PDF Full Text Request