期刊
BLOOD
卷 100, 期 2, 页码 594-602出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.V100.2.594
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- NCI NIH HHS [R01 CA70873, R01 CA80183] Funding Source: Medline
Up-regulation of folate receptor (FR) type-beta 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-beta 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-beta lacked mutations, and neither deglycosylation nor detergent solubilization restored folate binding. The posttranslational modification causing its nonfunctionality was evidently absent In FR-beta from AML cells from patient marrow, which bound folate, From flow cytometric analysis of 78 AML bone marrow specimens of different sub-types, 68% expressed FR-beta, 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-beta), 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-beta-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-beta (+) AMLs. (C) 2002 by The American Society of Hematology.
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