title: Orally active αvβ3 integrin inhibitor MK-0429 reduces melanoma metastasis.
abstract: Melanoma remains one of the most aggressive types of cancer with a historically low survival rate. The αvβ3 integrin is involved in the progression of malignant melanoma. In the present study, the efficacy of MK-0429, a selective inhibitor of the αvβ3 integrin, was evaluated for its potential in the prevention of melanoma metastasis. Female B6D2F1 mice injected via the tail vein with murine B16F10 melanoma developed lung metastases within ~10 days. In the first experiment, the prevention of lung metastasis was assessed in the model treated with either vehicle, MK-0429 at 100 and 300 mg/kg orally twice daily or cyclophosphamide at 300 mg/kg, i.p. once daily. Study endpoints included determination of the study time period to achieve metastasis in lungs in this model, evaluation of the health effects on the study animals, the total number of lung colonies identified and lung tumor area. Unlike cyclophosphamide, the MK-0429 treatment did not lead to a significant weight reduction in mice. MK-0429 at 100 and 300 mg/kg reduced the number of metastatic tumor colonies by 64 and 57%, respectively, and the high dose also reduced the tumor area by 60% as compared to the vehicle. The second experiment employed B16F10 luciferase-expressing cells to examine the de novo progression of melanoma metastasis over 15 days with bioluminescent imaging of mice treated with MK-0429 at 300 mg/kg as compared to the vehicle. Tumor burden progressively advanced in the lungs of the B16F10-treated animals. However, MK-0429 reduced the progression of ventral and dorsal lung metastases by 22 and 38%, respectively, as compared to the vehicle, by study completion. Quantification of ex vivo tumor burden showed a 30-40% reduction in lung colonies by MK-0429. The two studies collectively demonstrated that MK-0429 was safe and efficacious in significantly decreasing melanoma metastasis in the lungs. The results emphasized the potential of MK-0429 as a novel, therapeutic agent for the prevention of metastatic melanoma.
authors: Bone Biology, Merck Research Laboratories, West Point, PA 19486, USA.
authors: Maureen
authors: M
authors: Pickarski
authors: Imaging, Merck Research Laboratories, West Point, PA 19486, USA.
authors: Alexa
authors: A
authors: Gleason
authors: Imaging, Merck Research Laboratories, West Point, PA 19486, USA.
authors: Bohumil
authors: B
authors: Bednar
authors: Bone Biology, Merck Research Laboratories, West Point, PA 19486, USA.
authors: Le T
authors: LT
authors: Duong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009287:Naphthyridines / Q000008:administration & dosage*; D011422:Propionates / Q000008:administration & dosage*; D012878:Skin Neoplasms; D000096142:Cutaneous Malignant Melanoma
chemical_list: C478626:3-(6-methoxypyridin-3-yl)-3-(2-oxo-3-(3-(5,6,7,8-tetrahydro(1,8)naphthyridin-2-yl)propyl)imidazolidin-1-yl)propionic acid; D039302:Integrin alphaVbeta3; D009287:Naphthyridines; D011422:Propionates