Abstract
A6 is an eight amino acid peptide derived from the non-receptor binding region of urokinase plasminogen activator (uPA), which interferes with the uPA/uPA receptor system. A6 has been synthesized as a potential anti-angiogenic, anti-cancer agent. The current study has investigated the potential therapeutic activity of A6 in the Lewis lung carcinoma (3LL) model of pulmonary metastasis. A6 was found to have direct anti-tumor activity against established 3LL pulmonary metastases at a low tumor burden (10-20 colonies per lung) and was therapeutic in combination with cyclophosphamide at high tumor burdens (> 100 colonies per lung). Mechanistic studies have revealed that A6 directly inhibits the invasion of 3LL cells through a Matrigel model basement membrane by 40-45%. Moreover, treatment with either A6 or doxorubicin resulted in thicker tubes in endothelial tube formation studies. Our results suggest that A6, by virtue of its anti-invasive and anti-angiogenic properties, might work additively or synergistically with chemotherapeutic agents and thereby contribute to enhanced therapy of established 3LL cancer metastases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / therapeutic use*
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Animals
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Antineoplastic Agents / therapeutic use*
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Carcinoma, Lewis Lung / drug therapy*
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Carcinoma, Lewis Lung / metabolism
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Carcinoma, Lewis Lung / secondary
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Cyclophosphamide / therapeutic use
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Doxorubicin / therapeutic use
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Drug Synergism
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Drug Therapy, Combination
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism
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Endothelium, Vascular / pathology
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Humans
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In Vitro Techniques
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Mice
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Neoplasm Invasiveness / prevention & control
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Neoplasm Transplantation
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Neovascularization, Pathologic / prevention & control
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Peptide Fragments / therapeutic use*
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RNA, Messenger / metabolism
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Receptors, Urokinase Plasminogen Activator
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Reverse Transcriptase Polymerase Chain Reaction
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Tumor Cells, Cultured
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Urokinase-Type Plasminogen Activator / genetics
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Urokinase-Type Plasminogen Activator / metabolism
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Urokinase-Type Plasminogen Activator / therapeutic use*
Substances
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Angiogenesis Inhibitors
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Antineoplastic Agents
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PLAUR protein, human
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Peptide Fragments
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Plaur protein, mouse
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RNA, Messenger
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Receptors, Cell Surface
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Receptors, Urokinase Plasminogen Activator
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Doxorubicin
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Cyclophosphamide
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Urokinase-Type Plasminogen Activator