Combined chemo/anti-angiogenic cancer therapy against Lewis lung carcinoma (3LL) pulmonary metastases.
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.
Datta
Anjuli
A
Department of Molecular Biology and Immunology, Institute for Cancer Research, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107-2118, USA.
Kitson
Richard P
RP
Xue
Yaming
Y
al-Atrash
Gheath
G
Mazar
Andrew P
AP
Jones
Terence R
TR
Goldfarb
Ronald H
RH
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010446:Peptide Fragments / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C524898:PLAUR protein, human; D010446:Peptide Fragments; C524899:Plaur protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D004317:Doxorubicin; D003520:Cyclophosphamide; D014568:Urokinase-Type Plasminogen Activator