title: Mcl-1 is a novel therapeutic target for human sarcoma: synergistic inhibition of human sarcoma xenotransplants by a combination of mcl-1 antisense oligonucleotides with low-dose cyclophosphamide.
abstract: OBJECTIVE
  Little is known about the role that Mcl-1, an antiapoptotic Bcl-2 family member, plays in solid tumor biology and susceptibility to anticancer therapy. We observed that the Mcl-1 protein is widely expressed in human sarcoma cell lines of different histological origin (n = 7). Because the expression of antiapoptotic Bcl-2 family proteins can significantly contribute to the chemoresistance of human malignancies, we used an antisense strategy to address this issue in sarcoma.
  
  
  METHODS
  SCID mice (n = 6/group) received s.c. injections of SW872 liposarcoma cells. After development of palpable tumors, mice were treated by s.c.-implanted miniosmotic pumps prefilled with saline or antisense or universal control oligonucleotides (20 mg/kg/day for 2 weeks). On days 2, 6, and 10, mice were treated with low-dose cyclophosphamide (35 mg/kg i.p) or saline control. During the experiments, tumor weight was assessed twice weekly by caliper measurements. On day 14, animals were sacrificed. Tumors were weighed and fixed in formalin for immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling analysis.
  
  
  RESULTS
  Mcl-1 antisense oligonucleotides specifically reduced Mcl-1 protein expression but produced no reduction in tumor weight compared with saline-treated control animals. Cyclophosphamide monotreatment caused only modest tumor weight reduction compared with saline control. However, use of Mcl-1 antisense oligonucleotides combined with cyclophosphamide clearly enhanced tumor cell apoptosis and significantly reduced tumor weight by more than two-thirds compared with respective control treatments.
  
  
  CONCLUSIONS
  A combination of Mcl-1 antisense oligonucleotides with low-dose cyclophosphamide provides a synergistic antitumor effect and might qualify as a promising strategy to overcome chemoresistance in human sarcoma.
authors.affiliation: Department of Clinical Pharmacology, Section of Experimental Oncology/Molecular Pharmacology, University of Vienna, Vienna, Austria.
authors.forename: Christiane
authors.initials: C
authors.lastname: Thallinger
authors.forename: Markus F
authors.initials: MF
authors.lastname: Wolschek
authors.forename: Helmut
authors.initials: H
authors.lastname: Maierhofer
authors.forename: Hans
authors.initials: H
authors.lastname: Skvara
authors.forename: Hubert
authors.initials: H
authors.lastname: Pehamberger
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: Burkhard
authors.initials: B
authors.lastname: Jansen
authors.forename: Volker
authors.initials: V
authors.lastname: Wacheck
authors.forename: Edgar
authors.initials: E
authors.lastname: Selzer
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D016513:Mice, SCID; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009841:Oligonucleotides / Q000737:chemistry; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D013997:Time Factors
chemical_list: C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D003520:Cyclophosphamide; D019311:Staurosporine