Anti-metastatic properties of RGD-peptidomimetic agents S137 and S247.
Integrins expressed on endothelial cells modulate cell migration and survival during angiogenesis. Integrins expressed on carcinoma cells potentiate metastasis by facilitating invasion and movement across blood vessels. We describe the activities of two synthetic low-molecular-weight peptidomimetics of the ligand amino acid sequence arg-gly-asp (RGD) in integrin-based functional assays in vitro. We also evaluate efficacy and potential mechanisms of action in models of both spontaneous and experimental metastasis. Broad-spectrum potency against the family of alpha v subunit-containing integrins was observed, with significantly less potency against alpha5beta1 and alpha(IIb)beta3. Both endothelial and tumor cell migration mediated by alpha(v)beta3 was inhibited, whereas proliferation of endothelial cells but not tumor cells was diminished. Continuous infusion of compound by minipumps or oral administration twice daily significantly reduced metastatic tumor burden in the lungs of mice despite no reduction in growth of 435/HAL primary tumors, and only a slight reduction in tumor cells detected in circulating blood. Delaying treatment in this model until after extensive dissemination of tumor cells to the lungs had occurred, and after primary tumor resection, still produced significant efficacy. Conversely, administration of the agent for only the first 18 h after tumor-cell inoculation into the tail vein also resulted in decreased metastases observed after several weeks. These data suggest these compounds or their relatives have potential to interfere with both early and late steps of metastasis involving tumor and endothelial cell functions. Furthermore, the metastatic process can be effectively inhibited independently of primary tumor growth using integrin antagonists.
Shannon
Kristen E
KE
Pfizer Global Research and Development, Chesterfield, Missouri 63017, USA.
Keene
Jeffery L
JL
Settle
Steven L
SL
Duffin
Tiffany D
TD
Nickols
Maureen A
MA
Westlin
Marisa
M
Schroeter
Sally
S
Ruminski
Peter G
PG
Griggs
David W
DW
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000473:pathology*; D044584:Carcinoma, Ductal / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control / Q000556:secondary* / Q000601:surgery; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000637:transplantation; D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D015918:Infusion Pumps, Implantable; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000517:prevention & control / Q000556:secondary*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009360:Neoplastic Cells, Circulating; D009842:Oligopeptides; D009930:Organic Chemicals / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004151:Dipeptides; D039302:Integrin alphaVbeta3; D009363:Neoplasm Proteins; D009842:Oligopeptides; D009930:Organic Chemicals; D011743:Pyrimidines; C487379:S 137 compound; C474314:S 247 compound; C047981:arginyl-glycyl-aspartic acid