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Combination therapy using imatinib and vatalanib improves the therapeutic efficiency of paclitaxel towards a mouse melanoma tumor
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Department of Dermatology, Faculty of Medicine, University of Yamanashi, Shimokato, Tamaho, Nakakoma, Yamanashi, Japan.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
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2011 (English)In: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, Vol. 21, no 1, 57-65 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Wolters Kluwer Health | Lippincott Williams & Wilkins , 2011. Vol. 21, no 1, 57-65 p.
Keyword [en]
combination therapy, inhibitor, mouse melanoma, paclitaxel, receptor tyrosine kinase
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-119825DOI: 10.1097/CMR.0b013e32833faf4dISI: 000285709200006PubMedID: 20975605OAI: oai:DiVA.org:uu-119825DiVA: diva2:301025
Available from: 2010-03-02 Created: 2010-03-02 Last updated: 2012-03-14Bibliographically approved
In thesis
1. Combination Therapies Targeting PDGF and VEGF Signaling Pathways in Solid Tumors
Open this publication in new window or tab >>Combination Therapies Targeting PDGF and VEGF Signaling Pathways in Solid Tumors
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) are independently involved in several cancer-associated mechanisms including autocrine stimulation of cancer cells, stimulation of tumor angiogenesis and regulation of interstitial fluid pressure (IFP). The scope of this thesis was to investigate the combinatory effect of anti-VEGF and anti-PDGF treatment on tumor angiogenesis and tumor IFP.

Angiogenesis is a process of formation of blood vessels. Based on the tumors dependency on the blood vessels to supply them with oxygen and nutrients, several anti-angiogenic therapies have been tried and shown to have beneficial anti-tumor effects. More recently, anti-angiogenic treatment appeared to transiently “normalize” disorganized tumor vasculature and therefore to improve the uptake of cytotoxic agents.

In the first study, treatment was performed on two tumor models that differ only with regard to the degree of maturation of the vasculature, reflected by different number of pericytes that are the target for anti-PDGF treatment in these tumors. The aim was to study the role of pericyte coverage in protecting endothelial cells from anti-VEGF therapies. In the pericyte-rich tumor model the combination treatment gave a more efficient anti-angiogenic effect. Interestingly, it was only a subset of pericytes that was sensitive for the treatment.

In the second paper, the effect of anti-VEGF and anti-PDGF treatment on tumor IFP was measured. IFP is elevated in most solid tumors, which is linked to poor prognosis and higher recurrence rate. Additionally, this serves as a problem in ant-cancer therapies since it makes the uptake of cytotoxic agents inefficient. PDGF is known to actively regulate the IFP by regulating the contractile activity of fibroblasts, while VEGF regulates IFP primarily by affecting vessel leakiness. In the current study, combination of anti-VEGF and anti-PDGF therapies was shown to have an additive effect. However, the timing of administration of inhibitors appeared to be crucial. It was only short, but not long term combination treatment that further reduced IFP as compared to monotherapies. Surprisingly, the additive effect on IFP did not translate into an increased efficiency of chemotherapy when comparing combination treatment with monotherapies.

The last paper is a follow up of the first study, where it was shown that combination of anti-VEGF and anti-PDGF treatment affect the tumor vasculature. Here we investigated if the anti-angiogenic effect improves treatment efficiency of a cytotoxic agent. There was a significant effect of the combination of anti-VEGF and anti-PDGF on Taxol treatment efficiency in this Taxol resistant tumor model. However, the mechanism for the treatment effect and the relative contribution of the targeted vasculature in the outcome of the therapy remains to be determined, since tumor cells were also sensitized for Taxol in vitro.

In summary, we have shown that targeting of PDGF and VEGF signaling pathways simultaneously affect both vasculature and IFP to a higher extent than monotherapies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 527
National Category
Medical and Health Sciences
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-119827 (URN)978-91-554-7735-6 (ISBN)
Public defence
2010-04-09, B22, Uppsala Biomedical Center (BMC), Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2010-03-26 Created: 2010-03-02 Last updated: 2011-02-21Bibliographically approved

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