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Combination therapy using imatinib and vatalanib improves the therapeutic efficiency of paclitaxel towards a mouse melanoma tumor.

Abstract
Melanomas respond poorly to chemotherapy. In this study, we investigated the sensitization of B16 mouse melanoma tumors to paclitaxel by a combination of two tyrosine kinase inhibitors: vatalanib, targeting vascular endothelial growth factor receptors, and imatinib, an inhibitor targeting for example, Abl/BCR-ABL, the platelet-derived growth factor receptor, and stem cell factor receptor c-Kit. C57Bl6/J mice carrying B16/PDGF-BB mouse melanoma tumors were treated daily with vatalanib (25 mg/kg), imatinib (100 mg/kg), or a combination of these drugs. Paclitaxel was given subcutaneously twice during the study. The effects of the drugs on tumor cell proliferation in vitro were determined by counting cells. B16/PDGF-BB mouse melanoma tumors were not sensitive to paclitaxel at doses of either 5 or 20 mg/kg. However, the tumor growth was significantly reduced by 58%, in response to paclitaxel (5 mg/kg) when administered with daily doses of both vatalanib and imatinib. Paclitaxel only inhibited the in-vitro growth of B16/PDGF-BB tumor cells when given in combination with imatinib. Imatinib presumably targets c-Kit, as the cells do not express platelet-derived growth factor receptor and as another c-Abl inhibitor was without effect. This was supported by data from three c-Kit-expressing human melanoma cell lines showing varying sensitization to paclitaxel by the kinase inhibitors. In addition, small interfering RNA knockdown of c-Kit sensitized the cells to paclitaxel. These data show that combination of two tyrosine kinase inhibitors, imatinib and vatalanib, increases the effects of paclitaxel on B16/PDGF-BB tumors, thus suggesting a novel strategy for the treatment of melanomas expressing c-Kit.
AuthorsAgnieszka Kłosowska-Wardęga, Yoko Hasumi, Aive Åhgren, Carl-Henrik Heldin, Carina Hellberg
JournalMelanoma research (Melanoma Res) Vol. 21 Issue 1 Pg. 57-65 (Feb 2011) ISSN: 1473-5636 [Electronic] England
PMID20975605 (Publication Type: Journal Article)
Chemical References
  • Angiogenesis Inhibitors
  • Benzamides
  • Phthalazines
  • Piperazines
  • Proto-Oncogene Proteins c-sis
  • Pyridines
  • Pyrimidines
  • RNA, Small Interfering
  • platelet-derived growth factor BB
  • vatalanib
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-kit
  • Paclitaxel
Topics
  • Angiogenesis Inhibitors (administration & dosage)
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Benzamides (administration & dosage)
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Synergism
  • Imatinib Mesylate
  • Melanoma, Experimental (drug therapy)
  • Mice
  • Mice, Inbred C57BL
  • Paclitaxel (administration & dosage)
  • Phthalazines (administration & dosage)
  • Piperazines (administration & dosage)
  • Protein-Tyrosine Kinases (antagonists & inhibitors)
  • Proto-Oncogene Proteins c-kit (metabolism)
  • Proto-Oncogene Proteins c-sis (metabolism)
  • Pyridines (administration & dosage)
  • Pyrimidines (administration & dosage)
  • RNA, Small Interfering (metabolism)
  • Signal Transduction

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