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LY317615 decreases plasma VEGF levels in human tumor xenograft-bearing mice

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Abstract

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 TGFβ in nude mice. Mice bearing these human tumor xenografts were treated orally twice daily with the PKCβ 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-β 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 PKCβ 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 TGFβ were not markers of LY317615 activity.

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Abbreviations

bFGF:

Basic fibroblast growth factor

PKC-β:

Protein kinase C-beta

SCLC:

Small-cell lung cancer

TGD:

Tumor growth delay

TGF-β:

Transforming growth factor-beta

VEGF:

Vascular endothelial growth factor

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Author notes

  1. Kristan A. Keyes

    Present address: Millennium Pharmaceuticals, Inc., 75 Sidney St., Cambridge, MA 02139, USA

Authors and Affiliations

  1. Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA

    Kristan A. Keyes, Larry Mann, Michael Sherman, Elizabeth Galbreath, Linda Schirtzinger, Darryl Ballard, Yun-Fei Chen, Philip Iversen & Beverly A. Teicher

  2. Genzyme Corporation, 1 Mountain Road, Framingham, MA 01701-9322, USA

    Beverly A. Teicher

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  1. Kristan A. Keyes
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Correspondence to Beverly A. Teicher.

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Keyes, K.A., Mann, L., Sherman, M. et al. LY317615 decreases plasma VEGF levels in human tumor xenograft-bearing mice. Cancer Chemother Pharmacol 53, 133–140 (2004). https://doi.org/10.1007/s00280-003-0713-x

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