Antiangiogenic and Antitumor Effects of a Protein Kinase Cβ Inhibitor in Human Breast Cancer and Ovarian Cancer Xenografts
作者： Beverly A. Teicher , Krishna Menon , Enrique Alvarez , Chuan Shih , Margaret M. Faul
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摘要: In cell culture, the compound317615.2HCl, a potent inhibitor ofVEGF-stimulated HUVEC proliferation, wasnot very effective against MX-1 breastcancer cells (IC50 = 8.1 μM) orSKOV-3 ovarian carcinoma =9.5 μM). Exposure to combinations ofpaclitaxel or carboplatin and317615.2HCl with in cultureresulted survival that reflectedprimarily additivity of two agents.Exposure SKOV-3 paclitaxel orcarboplatin along 317615.2HClresulted survivals reflectedadditivity 317615.2HCl withpaclitaxel and greater-than-additivecytotoxicity carboplatin.Administration orallytwice daily nude mice bearingsubcutaneous tumors tumorsresulted decreased number ofintratumoral vessels as determined by CD31and CD105 staining decreases 35%and 43% 60% 75%in tumors, respectively.317615.2HCl was an active antitumoragent xenograft andincreased tumor growth delay producedby 1.7-fold tumorgrowth produced by3.8-fold. Administration of317615.2HCl also increased fractionatedradiation therapy tumor.Treatment aloneincreased lifespan animals bearingintraperitoneal xenografts 1.9fold compared untreated controlanimals. The combination resulted 100% 120-daysurvival bearing animals.Administration alongwith theSKOV-3 1.8-fold increasein carboplatinalone. is promising newantiangiogenic agent early phaseclinical testing.
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