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

Invest New Drugs. 2002 Aug;20(3):241-51. doi: 10.1023/a:1016297611825.


In cell culture, the compound 317615 2HCl, a potent inhibitor of VEGF-stimulated HUVEC proliferation, was not very effective against MX-1 breast cancer cells (IC50= 8.1 microM) or SKOV-3 ovarian carcinoma cells (IC50 = 9.5 microM). Exposure to combinations of paclitaxel or carboplatin and 317615 x 2HCl with MX-1 cells in culture resulted in cell survival that reflected primarily additivity of the two agents. Exposure of SKOV-3 cells to paclitaxel or carboplatin along with 317615 2HCl resulted in cell survivals that reflected additivity of 317615 x 2HCl with paclitaxel and greater-than-additive cytotoxicity with carboplatin. Administration of 317615 x 2HCI orally twice daily to nude mice bearing subcutaneous MX-1 tumors or SKOV-3 tumors resulted in a decreased number of intratumoral vessels as determined by CD31 and CD105 staining with decreases of 35% and 43% in MX-1 tumors and 60% and 75% in SKOV-3 tumors, respectively. 317615 x 2HCl was an active antitumor agent against the MX-1 xenograft and increased the tumor growth delay produced by paclitaxel by 1.7-fold and the tumor growth delay produced by carboplatin by 3.8-fold. Administration of 317615 x 2HCl also increased the tumor growth delay produced by fractionated radiation therapy in the MX-1 tumor. Treatment with 317615 x 2HCl alone increased the lifespan of animals bearing intraperitoneal SKOV-3 xenografts by 1.9 fold compared with untreated control animals. The combination of paclitaxel and 317615 x 2HCl resulted in 100% 120-day survival of SKOV-3 bearing animals. Administration of 317615 x 2HCl along with carboplatin to animals bearing the SKOV-3 tumor produced a 1.8-fold increase in lifespan compared with carboplatin alone. 317615 x 2HCl is a promising new antiangiogenic agent that is in early phase clinical testing.

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology*
  • Antineoplastic Agents, Alkylating / therapeutic use*
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / radiotherapy
  • Carboplatin / therapeutic use
  • Cell Survival / drug effects
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation / physiology
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / pathology
  • Organic Chemicals
  • Ovarian Neoplasms / blood supply
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / radiotherapy
  • Paclitaxel / therapeutic use
  • Protein Kinase C / antagonists & inhibitors*
  • Protein Kinase C beta
  • Regional Blood Flow / drug effects
  • Transplantation, Heterologous


  • 317615 x 2HCl
  • Angiogenesis Inhibitors
  • Antineoplastic Agents, Alkylating
  • Antineoplastic Agents, Phytogenic
  • Enzyme Inhibitors
  • Organic Chemicals
  • Carboplatin
  • Protein Kinase C
  • Protein Kinase C beta
  • Paclitaxel