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キーワード:
Angiogenesis Inhibitors/administration & dosage/*pharmacology
Animals
Antineoplastic Combined Chemotherapy Protocols/*pharmacology
Carcinoma, Non-Small-Cell Lung/*blood supply/*drug therapy/enzymology
Cell Line, Tumor
Drug Synergism
Humans
Lung Neoplasms/*blood supply/*drug therapy/enzymology
Male
Mass Spectrometry
Mice
Mice, Nude
Multimodal Imaging
Phthalazines/administration & dosage/pharmacology
Piperidines/administration & dosage/pharmacology
Positron-Emission Tomography
Protein Kinase Inhibitors/administration & dosage/*pharmacology
Pyridines/administration & dosage/pharmacology
Quinazolines/administration & dosage/pharmacology
Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors
Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors
Xenograft Model Antitumor Assays
要旨:
Extensive oncologic experience argues that the most efficacious applications of antiangiogenic agents rely upon a combination with cytotoxic drugs. Yet there remains a lack of clarity about how to optimize scheduling for such drug combinations. Prudent antiangiogenic therapy might transiently normalize blood vessels to improve tumor oxygenation and drug exposure. Using [(15)O]H2O positron emission tomography imaging in a preclinical mouse model of non-small cell lung cancer, we observed that short-term treatment with the vascular endothelial growth factor receptor/platelet-derived growth factor receptor inhibitor PTK787 licensed a transient window of improved tumor blood flow. The improvement observed was associated with a reduced leakiness from tumor vessels, consistent with induction of a vascular normalization process. Initiation of a cytotoxic treatment in this window of tumor vessel normalization resulted in increased efficacy, as illustrated by improved outcomes of erlotinib administration after initial PTK787 treatment. Notably, intermittent PTK787 treatment also facilitated long-term tumor regression. In summary, our findings offer strong evidence that short-term antiangiogenic therapy can promote a transient vessel normalization process that improves the delivery and efficacy of a targeted cytotoxic drug.
