title: Evaluation of antileukaemic effects of rapamycin in patients with imatinib-resistant chronic myeloid leukaemia.
abstract: BACKGROUND
  Recent data suggest that the mammalian target of rapamycin (mTOR) is involved in the regulation of growth of neoplastic cells in chronic myeloid leukaemia (CML).
  
  
  METHODS
  We treated six patients with imatinib-resistant CML in haematological relapse (leukocytes > 20,000 microL(-1)) with rapamycin at 2 mg per os daily for 14 consecutive days, with dose-adjustment allowed to reach a target rapamycin serum concentration of 10-20 pg mL(-1).
  
  
  RESULTS
  A major leukocyte response with decrease to less than 10,000 microL(-1) was obtained in two patients, and a minor transient response was seen in two other patients. In responding patients, we also observed a decrease in vascular endothelial growth factor (VEGF) mRNA levels in circulating leukaemic cells. Side effects during rapamycin treatment were mild in most patients. In one patient, pneumonia developed. Rapamycin was also found to counteract growth of CML cells in vitro as determined by (3)H-thymidine incorporation. Moreover, rapamycin inhibited the growth of Ba/F3 cells exhibiting various imatinib-resistant mutants of BCR/ABL, including the T315I variant that exhibits resistance against most currently available BCR/ABL kinase inhibitors.
  
  
  CONCLUSIONS
  Rapamycin shows antileukaemic effects in imatinib-resistant CML in vitro and in vivo. Larger trials with rapamycin or rapamycin-derivatives in combination with other targeted drugs are warranted to further determine clinical efficacy in CML.
authors.affiliation: Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Sillaber
authors.forename: M
authors.initials: M
authors.lastname: Mayerhofer
authors.forename: A
authors.initials: A
authors.lastname: Böhm
authors.forename: A
authors.initials: A
authors.lastname: Vales
authors.forename: A
authors.initials: A
authors.lastname: Gruze
authors.forename: K J
authors.initials: KJ
authors.lastname: Aichberger
authors.forename: H
authors.initials: H
authors.lastname: Esterbauer
authors.forename: M
authors.initials: M
authors.lastname: Pfeilstöcker
authors.forename: W R
authors.initials: WR
authors.lastname: Sperr
authors.forename: W F
authors.initials: WF
authors.lastname: Pickl
authors.forename: O A
authors.initials: OA
authors.lastname: Haas
authors.forename: P
authors.initials: P
authors.lastname: Valent
mesh_terms: D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D004341:Drug Evaluation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D020123:Sirolimus / Q000627:therapeutic use*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068877:Imatinib Mesylate; D020123:Sirolimus