title: CM101 treatment overrides tumor-induced immunoprivilege leading to apoptosis.
abstract: CM101, a bacterial polysaccharide exotoxin produced by group B Streptococcus (GBS), also referred to as GBS toxin, has been shown to target pathological neovasculature and activate complement (C3), thereby inducing neovascularitis, infiltration of inflammatory cells, inhibition of tumor growth, and apoptosis in murine tumor models. Data from refractory cancer patients in a Phase I clinical trial with CM101 indicated a similar mechanism of tumor-targeted inflammation. To further our understanding of the mechanism of action of CM101 as an antitumor agent, we examined the role of the inflammatory response in inducing tumor apoptosis in a normal mouse and tumor-bearing mouse model. The i.v. infusion of CM101 into B16BL-6 melanoma tumor-bearing mice elevated p53 mRNA in circulating leukocytes as measured by reverse transcription-PCR, and immunohistochemistry demonstrated infiltration and sequestration of leukocytes. Whole tumor lysates from excised tumors exhibited an increase in binding to the murine p21(Waf1/Cip1) derived p53 DNA binding sequence compared with control whole tumor lysates, in which minimal or no DNA binding was observed. CM101 infusion led to elevated levels of Fas protein within the tumors as well as a decrease in the expression of fas ligand (fasL). Furthermore, tumors were apoptotic as determined by terminal deoxynucleotidyl transferase-mediated nick end labeling and DNA fragmentation assays. Collectively, these data suggest that CM101 up-regulates p53 in tumor-infiltrating leukocytes, initiating a loss of tumor immunoprivilege and consequently rendering the tumor sensitive to Fas/fasL-mediated apoptosis. CM101 induced loss of tumor immunoprivilege through changes in the expression of leukocyte p53, tumor Fas and fasL coupled with neovascularitis and leukocyte infiltration, constitutes a plausible molecular pathway for tumor reduction observed in cancer patients.
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: F M
authors.initials: FM
authors.lastname: Yakes
authors.forename: B D
authors.initials: BD
authors.lastname: Wamil
authors.forename: F
authors.initials: F
authors.lastname: Sun
authors.forename: H P
authors.initials: HP
authors.lastname: Yan
authors.forename: C E
authors.initials: CE
authors.lastname: Carter
authors.forename: C G
authors.initials: CG
authors.lastname: Hellerqvist
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001427:Bacterial Toxins / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004273:DNA, Neoplasm / Q000276:immunology / Q000378:metabolism; D053222:Fas Ligand Protein; D016158:Genes, p53 / Q000187:drug effects / Q000235:genetics; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D011135:Polysaccharides, Bacterial / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation; D019014:fas Receptor / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001427:Bacterial Toxins; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011135:Polysaccharides, Bacterial; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; C032263:streptococcal polysaccharide type III group B; D018799:Intercellular Adhesion Molecule-1