ABSTRACT
Type II DNA topoisomerases (EC 5.99.1.3) are enzymes that catalyse topological changes in DNA in an ATP dependent manner. Strand passage reactions involve passing one double stranded DNA duplex (transported helix) through a transient enzyme-bridged break in another (gated helix). This activity is required for a range of cellular processes including transcription. Vertebrates have two isoforms: topoisomerase IIα and ß. Topoisomerase IIß was first reported in 1987. Here we review the research on DNA topoisomerase IIß over the 30 years since its discovery.
Subject(s)
DNA Topoisomerases, Type II/genetics , DNA Topoisomerases, Type II/metabolism , Research , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Cycle/genetics , Cloning, Molecular , DNA Topoisomerases, Type II/chemistry , DNA, Complementary/chemistry , DNA, Complementary/genetics , Gene Expression , Gene Expression Regulation , History, 20th Century , History, 21st Century , Humans , Intracellular Space/metabolism , Isoenzymes , Molecular Targeted Therapy , Protein Binding , Protein Transport , Research/history , Topoisomerase II Inhibitors/pharmacology , Topoisomerase II Inhibitors/therapeutic use , Transcriptional ActivationABSTRACT
The existence of tumor-specific T cells, as well as their ability to be primed in cancer patients, confirms that the immune response can be deployed to combat cancer. However, there are obstacles that must be overcome to convert the ineffective immune response commonly found in the tumor environment to one that leads to sustained destruction of tumor. Members of the tumor necrosis factor (TNF) superfamily direct diverse immune functions. OX40 and its ligand, OX40L, are key TNF members that augment T-cell expansion, cytokine production, and survival. OX40 signaling also controls regulatory T-cell differentiation and suppressive function. Studies over the past decade have demonstrated that OX40 agonists enhance antitumor immunity in preclinical models using immunogenic tumors; however, treatment of poorly immunogenic tumors has been less successful. Combining strategies that prime tumor-specific T cells together with OX40 signaling could generate and maintain a therapeutic antitumor immune response.
Subject(s)
Immunotherapy/methods , Neoplasms/immunology , Neoplasms/therapy , OX40 Ligand/immunology , Receptors, OX40/immunology , Signal Transduction/immunology , Animals , Antibodies, Monoclonal/therapeutic use , Cancer Vaccines , Combined Modality Therapy , Humans , Immunotherapy, Adoptive , Mice , OX40 Ligand/agonists , Receptors, OX40/agonists , T-Lymphocytes, Regulatory/immunologyABSTRACT
The immune-stimulatory properties of anti-CD134 (OX40) antibodies have been well documented in rodents, including their ability to enhance antitumor immunity. In this study, an anti-OX40 antibody (Ab) known to costimulate monkey T cells in vitro, was infused into rhesus macaque monkeys during immunization with the simian immunodeficiency virus protein, gp130. The draining lymph nodes from immunized monkeys treated with anti-OX40 were enlarged compared with immunized monkeys injected with mouse Ig. Anti-OX40-treated monkeys had increased gp130-specific Ab titers, and increased long-lived T-cell responses, compared with controls. There were no overt signs of toxicity in the anti-OX40-treated monkeys. The encouraging immune-stimulatory effects led to the good manufacturing practice production of an anti-OX40 Ab for clinical trials in cancer patients. A detailed toxicology study was performed with anti-OX40 in nonhuman primates. Three groups of 8 monkeys received anti-OX40 at 1 of 3 dose levels (0.4, 2.0, and 10 mg/kg) and a control group received saline. No clinical toxicity was observed, but acute splenomegaly and enlarged gut-associated lymph nodes were observed in the anti-OX40-treated animals; splenomegaly and lymphadenopathy resolved by day 28. These studies demonstrate the immune-stimulatory properties and safety of anti-OX40 in primates and provide a strong scientific rationale to pursue clinical trials in humans.
Subject(s)
Adjuvants, Immunologic/administration & dosage , Antibodies, Monoclonal/administration & dosage , Immunotherapy, Active/methods , Receptors, OX40/immunology , Adjuvants, Immunologic/pharmacokinetics , Adjuvants, Immunologic/toxicity , Animals , Antibodies/blood , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal/toxicity , Antigens, CD/metabolism , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cell Count , Female , Gene Products, env/immunology , Humans , Hyperplasia , Lymph Nodes/cytology , Lymph Nodes/drug effects , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Lymphocyte Count , Macaca fascicularis , Macaca mulatta , Male , Organ Size/drug effects , Receptors, OX40/metabolism , Spleen/drug effects , Spleen/immunology , Spleen/pathology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
Type XI collagen is a quantitatively minor yet essential constituent of the cartilage extracellular matrix. The amino propeptide of the alpha1 chain remains attached to the rest of the molecule for a longer period of time after synthesis than the other amino propeptides of type XI collagen and has been localized to the surface of thin collagen fibrils. Yeast two-hybrid system was used to demonstrate that a homodimer of alpha1(XI) amino propeptide (alpha1(XI)Npp) could form in vivo. Interaction was also confirmed using multi-angle laser light scattering, detecting an absolute weight average molar mass ranging from the size of a monomer to the size of a dimer (25,000-50,000 g/mol), respectively. Binding was shown to be saturable by ELISA. An interaction between recombinant alpha1(XI)Npp and the endogenous alpha1(XI)Npp was observed, and specificity for alpha1(XI)Npp but not alpha2(XI)Npp was demonstrated by co-precipitation. The interaction between the recombinant form of alpha1(XI)Npp and the endogenous alpha1(XI)Npp resulted in a stable association during the regeneration of cartilage extracellular matrix by fetal bovine chondrocytes maintained in pellet culture, generating a protein that migrated with an apparent molecular mass of 50-60 kDa on an SDS-polyacrylamide gel.
