dioleoyl-phosphatidylethanolamine and Melanoma

Patients with metastatic melanoma are immunosuppressed by the growing tumor. Allovectin-7 therapy is a form of active immunotherapy that aims at immunization of the host with substances designed to elicit an immune reaction that will eliminate or slow down the growth and spread of the cancer.. to describe the rationale for immunotherapy with Allovectin-7 and assess its safety profile and efficacy based on the results of completed melanoma clinical trials.. we reviewed both the published medical literature and the results of trials pending publication.. Allovectin-7 is a safe and active immunotherapeutic agent. It induces local and systemic durable responses in patients with metastatic melanoma.

Topics: Animals; beta 2-Microglobulin; Cancer Vaccines; Clinical Trials as Topic; DNA, Recombinant; Drug Screening Assays, Antitumor; Genetic Vectors; HLA-B7 Antigen; Humans; Immunotherapy, Active; Injections, Intralesional; Lipids; Lung Neoplasms; Macaca fascicularis; Melanoma; Mice; Phosphatidylethanolamines; Quaternary Ammonium Compounds; Skin Neoplasms; Tumor Escape; Vaccines, DNA

PTEN-positive tumors are not susceptible to the treatment with rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR). Here, we determined the susceptibility of PTEN-positive cells to small interfering RNA for mTOR (si-mTOR) by using a novel liposomal delivery system. We prepared dicetyl phosphate-tetraethylenepentamine-based polycation liposomes (TEPA-PCL) decorated with polyethylene glycol (PEG) grafting Ala-Pro-Arg-Pro-Gly (APRPG), a VRGFR-1-targeting peptide. APRPG-PEG-decorated TEPA-PCL carrying si-mTOR (APRPG-TEPA-PCL/si-mTOR) had an antiproliferative effect against B16F10 murine melanoma cells (PTEN-positive) and significantly inhibited both the proliferation and tube formation of mouse 2H-11 endothelial-like cells (PTEN-positive). APRPG-TEPA-PCL/si-mTOR treatment did not induce Akt phosphorylation (Ser473) in either B16F10 or 2H-11 cells although there was strong phosphorylation of Akt in response to rapamycin treatment. Intravenous injection of APRPG-TEPA-PCL/si-mTOR significantly suppressed the tumor growth compared with rapamycin treatment in mice bearing B16F10 melanoma. These findings suggest that APRPG-TEPA-PCL/si-mTOR is useful for the treatment of PTEN-positive tumors.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Animals; Cell Proliferation; Ethylenediamines; Liposomes; Male; Melanoma; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neovascularization, Pathologic; Phosphatidylethanolamines; Phosphorylation; Polyethylene Glycols; PTEN Phosphohydrolase; RNA, Small Interfering; TOR Serine-Threonine Kinases

In this study, we developed a nonviral, cationic, targeted DNA-carrier system by coupling SAINT/DOPE lipids to monoclonal antibodies. The two monoclonal antibodies used were both tumor specific, that is, MOC31 recognizes the epithelial glycoprotein EGP-2 present in carcinomas and Herceptin recognizes the HER-2/neu protein in breast and ovarian cancers. Coupling was performed under nonreducing conditions by covalent attachment. The coupling procedure appeared to be reproducible and the binding capacity of the antibody was not affected by linking them to the cationic lipid. Binding and transfection efficiency was assayed with target cells and nontarget cells. SAINT/DOPE lipoplexes as such appeared to be an effective transfection reagent for various cell lines. After coupling SAINT/DOPE to the monoclonal antibodies or F(ab)2 fragments, it was shown that the targeted MoAb-SAINT/DOPE lipoplexes preferably bound to target cells, compared to binding to the nontarget cells, especially for the Herceptin-SAINT/DOPE lipoplexes. More importantly, transfection of the target cells could also be improved with these targeted lipoplexes. In conclusion, we have shown that by using monoclonal antibody-coupled SAINT/DOPE lipoplexes cells targeted gene delivery can be achieved, and also a higher number of transfected target cells was seen.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cations; Cell Line, Tumor; DNA; Gene Targeting; Genetic Therapy; Humans; Immunoglobulin Fab Fragments; Lipid Metabolism; Liposomes; Melanoma; Mice; Neoplasms; Phosphatidylethanolamines; Plasmids; Skin Neoplasms; Transfection; Trastuzumab