Low-dose angiostatic tyrosine kinase inhibitors improve photodynamic therapy for cancer: lack of vascular normalization.
Photodynamic therapy (PDT) is an effective clinical treatment for a number of different cancers. PDT can induce hypoxia and inflammation, pro-angiogenic side effects, which may counteract its angio-occlusive mechanism. The combination of PDT with anti-angiogenic drugs offers a possibility for improved anti-tumour outcome. We used two tumour models to test the effects of the clinically approved angiostatic tyrosine kinase inhibitors sunitinib, sorafenib and axitinib in combination with PDT, and compared these results with the effects of bevacizumab, the anti-VEGF antibody, for the improvement of PDT. Best results were obtained from the combination of PDT and low-dose axitinib or sorafenib. Molecular analysis by PCR revealed that PDT in combination with axitinib suppressed VEGFR-2 expression in tumour vasculature. Treatment with bevacizumab, although effective as monotherapy, did not improve PDT outcome. In order to test for tumour vessel normalization effects, axitinib was also applied prior to PDT. The absence of improved PDT outcome in these experiments, as well as the lack of increased oxygenation in axitinib-treated tumours, suggests that vascular normalization did not occur. The current data imply that there is a future for certain anti-angiogenic agents to further improve the efficacy of photodynamic anti-cancer therapy.
Medical Photonics Group, Institute of Bioengineering, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland; Angiogenesis Laboratory, Department of Medical Oncology, VU Medical Center, Amsterdam, The Netherlands.
Andrea
A
Weiss
Judy R
JR
van Beijnum
Debora
D
Bonvin
Patrice
P
Jichlinski
Paul J
PJ
Dyson
Arjan W
AW
Griffioen
Patrycja
P
Nowak-Sliwinska
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D000068258:Bevacizumab; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D002645:Chickens; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D010778:Photochemotherapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D047428:Protein Kinase Inhibitors; D000068258:Bevacizumab
angiogenesis inhibitors; axitinib, bevacizumab; combination therapy; endothelial cells; photodynamic therapy; sorafenib; sunitinib; synergy; tyrosine kinase inhibitors