Squalamine treatment of human tumors in nu/nu mice enhances platinum-based chemotherapies.
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.
Williams
J I
JI
Magainin Pharmaceuticals Inc., Plymouth Meeting, Pennsylvania 19462, USA. Jwilliams@Magainin.com
Weitman
S
S
Gonzalez
C M
CM
Jundt
C H
CH
Marty
J
J
Stringer
S D
SD
Holroyd
K J
KJ
Mclane
M P
MP
Chen
Q
Q
Zasloff
M
M
Von Hoff
D D
DD
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
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