Squalamine treatment of human tumors in nu/nu mice enhances platinum-basedchemotherapies

Squalamine, an antiangiogenic aminosterol, is presently undergoing Phase II clinical trials in cancer patients. To broaden our understanding of the cl inical potential for squalamine, this agent was evaluated in nu/nu mouse xe nograft models using the chemoresistant MV-522 human non-small cell lung ca rcinoma and the SD human neuroblastoma lines. Squalamine was studied alone and in combination,vith either cisplatin or paclitaxel plus carboplatin, Sq ualamine alone produced a modest MV-522 tumor growth inhibition (TGI) and y ielded a TGI with cisplatin that was better than cisplatin alone. Squalamin e also significantly enhanced the activity of paclitaxel/carboplatin combin ation therapy in the MV-522 tumor model, Squalamine similarly improved the effectiveness of cisplatin in producing TGI when screened against the SD hu man neuroblastoma xenograft, Xenograft tumor shrinkage was seen for the R M V-522 tumor in combination treatments including squalamine, whereas no tumo r shrinkage was seen when squalamine was omitted from the treatment regimen . To gain a greater understanding of the mechanism by which squalamine inhi bited tumor growth in the xenograft studies, in vitro experiments were carr ied out with vascular endothelial growth factor-stimulated human umbilical vein endothelial cells in culture exposed to squalamine, Squalamine treatme nt was found to retard two cellular events necessary for angiogenesis, indu cing disorganization of F-actin stress fibers and causing a concomitant red uction of detectable cell the surface molecular endothelial cadherin (VE-ca dherin). We propose that the augmentation by squalamine of cytotoxicity fro m platinum-based therapies is attributable to interference by squalamine wi th the ability of stimuli to promote endothelial cell movement and cell-cel l communication necessary for growth of new blood vessels in xenografts aft er chemotherapeutic injury to the tumor.