Hypersensitivity of Ph-positive lymphoid cell lines to rapamycin: Possible clinical application of mTOR inhibitor.
The BCR/ABL tyrosine kinase inhibitor, imatinib mesylate, has shown substantial effects in chronic myelogenous leukemia (CML) and Ph-positive acute lymphoblastic leukemia (Ph(+)ALL). However, most patients relapse after an initial clinical response, indicating that drug resistance is a major problem in patients on imatinib. It is a serious problem that effective treatment choices to T315I, in the ABL kinase domain that shows a strong tolerance in imatinib do not exist clinically. In this study, we propose a new therapeutic approach to Ph(+)ALL with the T315I. Here, we report that the serine/threonine kinase mTOR (the mammalian target of rapamycin) inhibitor, rapamycin, inhibits the growth of not only the Bcr-Abl-positive lymphoid leukemic cell line, SU-Ph2, established from Ph(+)ALL patients, but also the imatinib-resistant cell line, SU/SR, that has acquired T315I. Rapamycin significantly inhibits cell growth in both these cell lines, and easily induces apoptosis at the same dose, thereby acting as an immunosuppressive agent. Our result suggested that the mTOR-signaling pathway has become an important therapeutic target for Ph-positive leukemias in the future, and at the same time, it is also becoming a very effective tool for the treatment of Ph(+)ALL with T315I.
Hirase
Chikara
C
Division of Hematology, Department of Internal Medicine, Kinki University School of Medicine, Osaka, Japan.
Maeda
Yasuhiro
Y
Takai
Shunsuke
S
Kanamaru
Akihisa
A
D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011494:Protein Kinases; D011743:Pyrimidines / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus