title: Squalamine treatment of human tumors in nu/nu mice enhances platinum-based chemotherapies.
abstract: Squalamine, an antiangiogenic aminosterol, is presently undergoing Phase II clinical trials in cancer patients. To broaden our understanding of the clinical potential for squalamine, this agent was evaluated in nu/nu mouse xenograft models using the chemoresistant MV-522 human non-small cell lung carcinoma and the SD human neuroblastoma lines. Squalamine was studied alone and in combination with either cisplatin or paclitaxel plus carboplatin. Squalamine alone produced a modest MV-522 tumor growth inhibition (TGI) and yielded a TGI with cisplatin that was better than cisplatin alone. Squalamine also significantly enhanced the activity of paclitaxel/carboplatin combination therapy in the MV-522 tumor model. Squalamine similarly improved the effectiveness of cisplatin in producing TGI when screened against the SD human neuroblastoma xenograft. Xenograft tumor shrinkage was seen for the MV-522 tumor in combination treatments including squalamine, whereas no tumor shrinkage was seen when squalamine was omitted from the treatment regimen. To gain a greater understanding of the mechanism by which squalamine inhibited tumor growth in the xenograft studies, in vitro experiments were carried out with vascular endothelial growth factor-stimulated human umbilical vein endothelial cells in culture exposed to squalamine. Squalamine treatment was found to retard two cellular events necessary for angiogenesis, inducing disorganization of F-actin stress fibers and causing a concomitant reduction of detectable cell the surface molecular endothelial cadherin (VE-cadherin). We propose that the augmentation by squalamine of cytotoxicity from platinum-based therapies is attributable to interference by squalamine with the ability of stimuli to promote endothelial cell movement and cell-cell communication necessary for growth of new blood vessels in xenografts after chemotherapeutic injury to the tumor.
authors: Magainin Pharmaceuticals Inc., Plymouth Meeting, Pennsylvania 19462, USA. Jwilliams@Magainin.com
authors: J I
authors: JI
authors: Williams
authors: S
authors: S
authors: Weitman
authors: C M
authors: CM
authors: Gonzalez
authors: C H
authors: CH
authors: Jundt
authors: J
authors: J
authors: Marty
authors: S D
authors: SD
authors: Stringer
authors: K J
authors: KJ
authors: Holroyd
authors: M P
authors: MP
authors: Mclane
authors: Q
authors: Q
authors: Chen
authors: M
authors: M
authors: Zasloff
authors: D D
authors: DD
authors: Von Hoff
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D015820:Cadherins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D002448:Cell Adhesion; D002478:Cells, Cultured; D002777:Cholestanols / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D017671:Platinum Compounds / Q000627:therapeutic use*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins / Q000166:cytology; D000099152:Cadherin 5
chemical_list: D000199:Actins; D016588:Anticarcinogenic Agents; D015703:Antigens, CD; D000970:Antineoplastic Agents; D015820:Cadherins; D002777:Cholestanols; D002945:Cisplatin; D017671:Platinum Compounds; D000099152:Cadherin 5; C079655:squalamine