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Blood, 15 July 2002, Vol. 100, No. 2, pp. 594-602
NEOPLASIA
Strategy for the treatment of acute myelogenous leukemia based on
folate receptor  -targeted liposomal doxorubicin combined with
receptor induction using all-trans retinoic
acid
Xing Q. Pan,
Xuan Zheng,
Guangfeng Shi,
Huaqing Wang,
Manohar Ratnam, and
Robert J. Lee
From the Division of Pharmaceutics, The Ohio State
University, Columbus, and the Department of Biochemistry and Molecular
Biology, Medical College of Ohio, Toledo.
Up-regulation of folate receptor (FR) type- 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- 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- lacked mutations, and neither deglycosylation nor detergent solubilization restored folate binding. The posttranslational modification causing its
nonfunctionality was evidently absent in FR- 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-,
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-), 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--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- (+) AMLs.
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