Antiangiogenic and antitumor effects of a protein kinase Cbeta inhibitor in human breast cancer and ovarian cancer xenografts

In cell culture, the compound317615^.2HCl, a potent inhibitor ofVEGF-stimulated HUVEC proliferation, wasnot very effective against MX-1 breastcancer cells (IC₅₀ = 8.1 M) orSKOV-3 ovarian carcinoma cells (IC₅₀ =9.5 M). Exposure to combinations ofpaclitaxel or carboplatin and317615^.2HCl with MX-1 cells in cultureresulted in cell survival that reflectedprimarily additivity of the two agents.Exposure of SKOV-3 cells to paclitaxel orcarboplatin along with 317615^.2HClresulted in cell survivals that reflectedadditivity of 317615^.2HCl withpaclitaxel and greater-than-additivecytotoxicity with carboplatin.Administration of 317615^.2HCl orallytwice daily to nude mice bearingsubcutaneous MX-1 tumors or SKOV-3 tumorsresulted in a decreased number ofintratumoral vessels as determined by CD31and CD105 staining with decreases of 35%and 43% in MX-1 tumors and 60% and 75%in SKOV-3 tumors, respectively.317615^.2HCl was an active antitumoragent against the MX-1 xenograft andincreased the tumor growth delay producedby paclitaxel by 1.7-fold and the tumorgrowth delay produced by carboplatin by3.8-fold. Administration of317615^.2HCl also increased the tumorgrowth delay produced by fractionatedradiation therapy in the MX-1 tumor.Treatment with 317615^.2HCl aloneincreased the lifespan of animals bearingintraperitoneal SKOV-3 xenografts by 1.9fold compared with untreated controlanimals. The combination of paclitaxel and317615^.2HCl resulted in 100% 120-daysurvival of SKOV-3 bearing animals.Administration of 317615^.2HCl alongwith carboplatin to animals bearing theSKOV-3 tumor produced a 1.8-fold increasein lifespan compared with carboplatinalone. 317615^.2HCl is a promising newantiangiogenic agent that is in early phaseclinical testing.