Preliminary in vivo evaluation of the protein transduction domain-modified ATTEMPTS approach in enhancing asparaginase therapy.

Full Abstract

Asparaginase (ASNase) is an enzyme drug presently approved for the induction of remission in the treatment of patients with acute lymphoblastic leukemia (ALL). The cytotoxic effect of ASNase is derived from its ability to deplete asparagine, an essential amino acid required by certain types of leukemia cells for protein synthesis and survival. Despite its efficacy in enhancing disease remission rate and prolonging complete remission duration in ALL patients, ASNase therapy is nevertheless confounded by a number of serious toxic effects, particularly to organs associated with high protein production (e.g., liver, pancreas), due to the systemic depletion of asparagine. Presented herein is a modified version of our previously established ATTEMPTS protein delivery system that carries the potential to permit a tumor specific, intracellular delivery of ASNase, thereby allowing for a significant reduction of ASNase-induced systemic toxicity. In a previous paper, we already demonstrated the in vitro feasibility of this heparin/protamine-regulated, TAT-mediated system in delivering ASNase directly into ASNase-sensitive murine lymphoma cells. In this article, we further validated the in vivo applicability of this system in animals harboring ASNase-encapsulated L5178Y lymphoma cells. Preliminary results showed that animals inoculated with L5178Y cells containing TAT-ASNase exhibited an extended survival rate of approximately 13% over those harboring L5178Y cells without the encapsulation of ASNase. Furthermore, the TAT-ASNase-treated mice also displayed a significantly improved hematological and liver histological status than the control groups. These findings bring promise to the use of the modified ATTEMPTS delivery system in achieving enhanced ASNase therapy.

Author information

Author/s: Li, Yong Tao (YT); Kwon, Young Min (YM); Spangrude, Gerald J (GJ); Liang, Jun F (JF); Chung, Hee Sun (HS); Park, Yoon Jeong (YJ); Yang, Victor C (VC);

Affiliation: Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin 300072, People's Republic of China.

Grants: R01 CA114612 (Agency:NCI NIH HHS) ; R01 HL55461 (Agency:NHLBI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: Journal of biomedical materials research. Part A (J Biomed Mater Res A), published in United States. (Language: eng)

Reference: 2009-Oct; vol 91 (issue 1) : pp 209-20

Dates: Created 2009/08/26; Completed 2009/11/02;

PMID: 18814276, status: MEDLINE (last retrieval date: 11/2/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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