LY317615 decreases plasma VEGF levels in human tumor xenograft-bearing mice.
Angiogenesis plays an important role in tumor growth. Angiogenic growth factors may be useful as biomarkers of antiangiogenic activity since their plasma concentrations correlate with the efficacy of treatments directed toward angiogenic targets. SW2 small-cell lung carcinoma (SCLC), Caki-1 renal cell carcinoma and HCT-116 colon carcinoma tumors produce measurable plasma VEGF, bFGF and TGFbeta in nude mice. Mice bearing these human tumor xenografts were treated orally twice daily with the PKCbeta inhibitor, LY317615 (days 14-30 for SW2 and HCT116, and days 21-39 for Caki-1). Plasma was collected every 3 days from control and treated mice. LY317615 significantly decreased plasma VEGF levels in mice bearing SW2 SCLC and Caki-1 renal cell carcinoma compared to control plasma concentrations beginning 5-7 days after initiating therapy. VEGF plasma levels remained suppressed after termination of LY317615 treatment and for the duration of the study (an additional 2 to 3 weeks). Plasma VEGF levels in mice bearing HCT116 xenografts were not altered by LY317615 treatment and plasma bFGF and TGF-beta were not altered by LY317615 in any of the animals. As shown by CD31 immunohistochemical staining, LY317615 decreased intratumoral vessel density by nearly 40% in all three tumors. Only the Caki-1 tumor responded to single-agent LY317615 therapy with a measurable tumor growth delay. Thus, unexpectedly inhibition of PKCbeta in vivo led to decreased VEGF production that persisted after therapy as well as to decreased intratumoral vessels. Plasma VEGF was a weak marker of response to LY317615, and plasma bFGF and TGFbeta were not markers of LY317615 activity.
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Kristan A
KA
Keyes
Larry
L
Mann
Michael
M
Sherman
Elizabeth
E
Galbreath
Linda
L
Schirtzinger
Darryl
D
Ballard
Yun-Fei
YF
Chen
Philip
P
Iversen
Beverly A
BA
Teicher
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012039:Regional Blood Flow; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D011493:Protein Kinase C