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
| Autor: | Robert J. Lee, Guangfeng Shi, Xuan Zheng, Manohar Ratnam, Huaqing Wang, Xing Q. Pan |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
medicine.medical_specialty
Myeloid Immunology Drug Evaluation Preclinical Retinoic acid Antigens CD34 Receptors Cell Surface Tretinoin Biology Biochemistry Mice chemistry.chemical_compound Drug Delivery Systems Folic Acid Internal medicine Antineoplastic Combined Chemotherapy Protocols Tumor Cells Cultured medicine Animals Humans education Folate receptor beta education.field_of_study Cell Death Chinese hamster ovary cell Folate Receptors GPI-Anchored Cell Biology Hematology medicine.disease Survival Rate Disease Models Animal Leukemia Myeloid Acute Leukemia Treatment Outcome medicine.anatomical_structure Endocrinology Gene Expression Regulation Therapeutic Equivalency chemistry Doxorubicin Folate receptor Liposomes Cancer research Bone marrow Carrier Proteins medicine.drug |
| Zdroj: | Blood. 100:594-602 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Up-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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|