Showing papers by "Rod Balhorn published in 2008"

Update: Systemic Radiotherapy Can Cure Lymphoma: A Paradigm for Other Malignancies?

Abstract: The cytocidal potency of a molecule can be augmented by conjugating a radionuclide for molecular targeted radionuclide therapy (MTRT) for cancer. Radioimmunotherapy (RIT) should be incorporated into the management of patients with B-cell non-Hodgkin's lymphoma (NHL) soon after the patients have proven incurable. Better drugs, strategies, and combinations with other drugs seem certain to make RIT integral to the management of patients with NHL and likely to lead to a cure of the currently incurable NHL. These improved drugs, strategies, and combinations thereof also offer opportunities for RIT to become part of the management of solid malignancies, including epithelial cancers. Smaller radionuclide carriers, such as those used for pretargeted strategies, provide dose intensification. The potential of pretargeted RIT to improve patient outcomes is striking.

Nanomolecular HLA-DR10 Antibody Mimics : A Potent System for Molecular Targeted Therapy and Imaging

Abstract: To mimic the molecular specificity and cell selectivity of monoclonal antibody (mAb) binding while decreasing size, nanomolecules (selective high-affinity ligands; SHALs), based on in silico modeling, have been created to bind to human leukocyte antigen-DR (HLA-DR10), a signaling receptor protein upregulated on the malignant B-lymphocytes of non-Hodgkin's lymphoma and chronic lymphocytic leukemia. SHALs were synthesized with a biotin or DOTA chelate (1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid), using a solid-phase lysine-polyethyleneglycol backbone to link sets of ligands shown previously to bind to HLA-DR10. Using cell-binding and death assays and confocal microscopy, SHAL uptake, residualization, and cytocidal activity were evaluated in HLA-DR10 expressing and nonexpressing live, human lymphoma cell lines. All of the SHALs tested were selective for, and accumulated in, expressing cells. Reflecting binding to HLA-DR10 inside the cells, SHALs having the Ct ligand (3-(2-([3-chloro-5-trifluoromethyl)-2-pyridinyl]oxy)-anilino)-3-oxopropanionic acid) residualized in expressing cells greater than 179 times more than accountable by cell-surface membrane HLA-DR10. Confocal microscopy confirmed the intracellular residualization of these SHALs. Importantly, SHALs with a Ct ligand had direct cytocidal activity, similar in potency to that of Lym-1 mAb and rituximab, selectively for HLA-DR10 expressing lymphoma cells and xenografts. The results show that SHALs containing the Ct ligand residualize intracellularly and have cytocidal effects mediated by HLA-DR10. These SHALs have extraordinary potential as novel molecules for the selective targeting of lymphoma and leukemia for molecular therapy and imaging. Further, these SHALs can be used to transport and residualize cytotoxic agents near critical sites inside these malignant cells.

Identification of a thermo-regulated glutamine-binding protein from Yersinia pestis.

Abstract: Here we present modeling and NMR spectroscopic evidence that the function of a Yersinia pestis pMT1 plasmid protein, designated as orf38, is most likely a glutamine binding protein. The modeling was homology-based at a very low level of sequence identity (∼ 16%) and involved structural comparison of multiple templates, as well as template-substrate interaction analyses. Transferred nuclear Overhauser and saturation transfer difference experiments were used to characterize the binding of sugars and amino acids to orf38. The identification and characterization of an unknown protein function using the strategy presented here has applicability to a variety of research areas, including functional genomics and proteomics efforts.