title: Comparison of a treatment strategy combining CCI-779 plus DTIC versus DTIC monotreatment in human melanoma in SCID mice.
abstract: This study compares the antineoplastic potential of a novel treatment strategy combining cell cycle inhibitor-779 (CCI-779) plus dacarbazine (DTIC) versus DTIC monotreatment, the current chemotherapeutic mainstay in combating metastatic melanoma. A controlled four-group parallel study design comprising 24-40 mice per tumor cell line was used in a severe combined immunodeficiency (SCID)-mouse xenotransplantation model. SCID mice were injected with 518A2, Mel-JUSO, or 607B human melanoma cells. After they developed tumors, mice received daily CCI-779 or solvent over 14 days. From treatment day 4-8 mice were additionally injected with DTIC or saline. Treatment with CCI-779 plus DTIC was superior to single agent DTIC in two out of three cell lines (P<0.05). The tumor weight reduction was 44+/-17 and 61+/-6% compared with DTIC monotreatment in Mel-JUSO and 607B melanomas, respectively (P<0.05). In contrast, in 518A2 xenotransplants, CCI-779 plus DTIC treatment was as effective as DTIC monotreatment. CCI-779 monotherapy exerted no statistically significant antitumor effect. Collectively, these data indicate that CCI-779 has the potential to increase the chemotherapeutic efficacy, as the combination of CCI-779 plus DTIC proved to be more efficacious compared to DTIC monotherapy in two out of three melanoma cell lines in vivo.
authors.affiliation: Division of Clinical Pharmacokinetics, Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria.
authors.forename: Christiane
authors.initials: C
authors.lastname: Thallinger
authors.forename: Johannes
authors.initials: J
authors.lastname: Werzowa
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Poeppl
authors.forename: Florian M
authors.initials: FM
authors.lastname: Kovar
authors.forename: Barbara
authors.initials: B
authors.lastname: Pratscher
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
authors.forename: Peter
authors.initials: P
authors.lastname: Quehenberger
authors.forename: Christian
authors.initials: C
authors.lastname: Joukhadar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D003606:Dacarbazine / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; C401859:temsirolimus; D003606:Dacarbazine; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; D020123:Sirolimus