Targeted 177 Lu antisense radiotherapy of B-cell non-Hodgkin's lymphoma

Title from PDF of title page (University of Missouri--Columbia, viewed on May 22, 2012).The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.Dissertation advisor: Dr. Michael R. LewisVita.Includes bibliographical references."July 2011"[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] The B-cell lymphoma/leukemia-2 (bcl-2) proto-oncogene in non-Hodgkin's lymphoma (NHL) is a dominant inhibitor of apoptosis. The research goal was to develop a [superscript 177]Lu-labeled bcl-2 antisense peptide nucleic acid (PNA)-peptide conjugate designed for dual modality NHL therapy, consisting of a radiopharmaceutical capable of simultaneously down-regulating apoptotic resistance and delivering cytotoxic internally emitted radiation. In vitro results demonstrated [superscript 177]Lu-DOTA-anti-bcl-2-Tyr[superscript 3]-octreotate uptake in Mec-1 NHL cells. An in vitro dosimetry model was generated with the resulting data. Proliferation and viability assays of mass and absorbed dose indicated a mass-dose dependence and that [superscript 177]Lu-bcl-2 antisense PNA-Tyr[superscript 3]-octreotate acted additively in effecting decreased cell viability with increasing radiation doses. In vivo receptor saturation studies determined the mass of the compound necessary to saturate tumors, providing maximal compound uptake and antisense potential. Biodistribution data showed specific tumor targeting of the radiolabeled PNA-peptide in Mec-1 xenografts, which was compared to the radiolabeled peptide [superscript 177]Lu-DOTA-Tyr[superscript 3]-octreotate. In vivo dosimetry modeling calculated normalized tumor absorbed doses that would be below the 2 Gy bone marrow margin of safety. Therapy studies showed modest tumor growth delay for treatment with the [superscript 177]Lu-labeled PNA peptide. A comparison of the efficacy of a pulse/chase injection versus a single injection of the compound is also discussed