title: CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells.
abstract: Patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) have poor prognosis despite intensive therapeutic intervention. Recently, imatinib, a BCR-ABL tyrosine kinase inhibitor, has been proven to be an effective treatment for Ph(+) ALL, but nearly all patients rapidly acquire resistance. High-dose imatinib administration might overcome this resistance; however, systemic toxicities would likely limit this approach. Therefore, a new delivery system allowing for the specific targeting of imatinib is urgently needed. Because almost all Ph(+) ALL cells express CD19 on their surface, we have developed an immunoliposome carrying anti-CD19 antibody (CD19-liposomes). The internalization efficiency of the CD19-liposomes approached 100% in all Ph(+) ALL cells but was very low in CD19(-) cells. The cytocidal effect of imatinib-encapsulated CD19-liposomes (imatinib-CD19-liposomes) on Ph(+) ALL cell lines and primary leukemia cells from patients with Ph(+) ALL was much greater than that of imatinib with or without control liposomes. Importantly, the imatinib-CD19-liposomes did not affect the colony formation of CD34(+) hematopoietic cells, even at inhibitory concentration of free imatinib. Taken together, these data clearly demonstrate that the imatinib-CD19-liposomes induced specific and efficient death of Ph(+) ALL cells. This new therapeutic approach might be a useful treatment for Ph(+) ALL with fewer side effects than free imatinib.
authors.affiliation: Department of Advanced Molecular and Cell Therapy, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Harata
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Soda
authors.forename: Kenzaburo
authors.initials: K
authors.lastname: Tani
authors.forename: Jun
authors.initials: J
authors.lastname: Ooi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takizawa
authors.forename: Minghan
authors.initials: M
authors.lastname: Chen
authors.forename: Yuansong
authors.initials: Y
authors.lastname: Bai
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Izawa
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Akira
authors.initials: A
authors.lastname: Tomonari
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Nagamura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Uchimaru
authors.forename: Tohru
authors.initials: T
authors.lastname: Iseki
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsuji
authors.forename: Tsuneo A
authors.initials: TA
authors.lastname: Takahashi
authors.forename: Kanji
authors.initials: K
authors.lastname: Sugita
authors.forename: Shinpei
authors.initials: S
authors.lastname: Nakazawa
authors.forename: Arinobu
authors.initials: A
authors.lastname: Tojo
authors.forename: Kazuo
authors.initials: K
authors.lastname: Maruyama
authors.forename: Shigetaka
authors.initials: S
authors.lastname: Asano
mesh_terms: D018941:Antigens, CD19 / Q000378:metabolism*; D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D002051:Burkitt Lymphoma; D016923:Cell Death / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D015473:Leukemia, Promyelocytic, Acute; D008081:Liposomes / Q000378:metabolism; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D018941:Antigens, CD19; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; D008081:Liposomes; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate