Strategy for the treatment of acute myelogenous leukemia based on folate receptor β–targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid
10.1182/blood.v100.2.594
Crossref journal-article
American Society of Hematology
Blood (234)
Abstract

AbstractUp-regulation of folate receptor (FR) type-β in acute myelogenous leukemia (AML) by all-trans retinoic acid (ATRA) and its restricted normal tissue distribution makes it a potential target for therapeutic intervention. The FR-β in peripheral blood granulocytes was unable to bind folate and appeared to have a variant GPI membrane anchor, evident from its insensitivity to phosphatidylinositol-specific phospholipase C but not nitrous acid. Granulocyte FR-β lacked mutations, and neither deglycosylation nor detergent solubilization restored folate binding. The posttranslational modification causing its nonfunctionality was evidently absent in FR-β from AML cells from patient marrow, which bound folate. From flow cytometric analysis of 78 AML bone marrow specimens of different subtypes, 68% expressed FR-β, most of which were also CD34+. In model cell lines that are FR (−) (KG-1a, L1210, and Chinese hamster ovary [CHO]) or FR (+) (KG-1, L1210 JF, and recombinant CHO-FR–β), selective FR-mediated binding and cytotoxicity was obtained using folate-coated liposomes encapsulating fluorescent calcein (f-L-calcein) and doxorubicin (f-L-DOX), respectively, which could be blocked by 1 mM free folic acid. In the FR-β–expressing KG-1 human AML cells, treatment with ATRA further increased this specificity. In mouse ascites leukemia models generated using L1210JF or KG-1 cells, increased median survival times were obtained with f-L-DOX treatment compared to nontargeted L-DOX. In the KG-1 model, ATRA treatment increased the cure rate with f-L-DOX from 10% to 60%. The above combined data from our 2 laboratories further support the feasibility and potential usefulness of selective ATRA-facilitated liposomal drug delivery in FR-β (+) AMLs.

Bibliography

Pan, X. Q., Zheng, X., Shi, G., Wang, H., Ratnam, M., & Lee, R. J. (2002). Strategy for the treatment of acute myelogenous leukemia based on folate receptor β–targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid. Blood, 100(2), 594–602.

Authors 6
  1. Xing Q. Pan (first)
  2. Xuan Zheng (additional)
  3. Guangfeng Shi (additional)
  4. Huaqing Wang (additional)
  5. Manohar Ratnam (additional)
  6. Robert J. Lee (additional)
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Dates
Type When
Created 22 years, 10 months ago (Oct. 1, 2002, 5:48 p.m.)
Deposited 4 years, 2 months ago (May 28, 2021, 8:37 a.m.)
Indexed 3 weeks ago (Aug. 5, 2025, 8:29 a.m.)
Issued 23 years, 1 month ago (July 15, 2002)
Published 23 years, 1 month ago (July 15, 2002)
Published Print 23 years, 1 month ago (July 15, 2002)
Funders 0

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@article{Pan_2002, title={Strategy for the treatment of acute myelogenous leukemia based on folate receptor β–targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid}, volume={100}, ISSN={0006-4971}, url={http://dx.doi.org/10.1182/blood.v100.2.594}, DOI={10.1182/blood.v100.2.594}, number={2}, journal={Blood}, publisher={American Society of Hematology}, author={Pan, Xing Q. and Zheng, Xuan and Shi, Guangfeng and Wang, Huaqing and Ratnam, Manohar and Lee, Robert J.}, year={2002}, month=jul, pages={594–602} }