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

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI-COLUMBIA AT AUTHOR'S REQUEST.] 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.

Name thesis:degree_name

Ph. D.

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Veterinary pathobiology (MU)

Grantor dc:publisher

University of Missouri--Columbia

Year dc:date.issued

2011

Author dc:creator

• Balkin, Ethan R., 1978-

Advisor dc:contributor.advisor

• Lewis, Michael R.

• antisense radiotherapy
• B-cell lymphoma-2
• peptide nucleic acid
• cancer therapy

Statement dc:rights

• Access to files is limited to the University of Missouri--Columbia with SSO login.

Language dc:language.iso

eng, English

DOI

https://doi.org/10.32469/10355/14295

OAI identifier oai:identifier

oai:mospace.umsystem.edu:10355/14295