Antiangiogenic effects of a protein kinase Cbeta-selective small molecule.

Abstract

BACKGROUND:

Protein kinase C frequently plays a central role in the intracellular signal transduction of growth factors and cytokines.

METHODS:

The acyclic bisindolylmaleimide 317615 x 2HCl was identified as a potent selective inhibitor of protein kinase Cbeta. The compound 317615 x 2HCl was tested in culture and in vivo in the rat corneal micropocket and in the SW2 small-cell lung carcinoma human tumor xenograft.

RESULTS:

In cell culture, 317615 x 2HCl was a more potent inhibitor of VEGF-stimulated HUVEC proliferation (IC50 150 nM, 72 h) than of human SW2 small-cell lung carcinoma cell proliferation (IC50 3.5 microM, 72 h). When administered orally twice daily for 10 days, the compound 317615 x 2HCl markedly decreased the neoangiogenesis induced by VEGF or bFGF in the rat corneal micropocket assay. To assess antitumor efficacy, 317615 x 2HCl was administered orally twice daily to nude mice bearing SW2 xenograft tumors on days 14 through 30 after tumor implantation. The number of countable intratumoral vessels was decreased in a dose-dependent manner reaching as low as one-quarter the number in the control tumors. The decrease in intratumoral vessels was paralleled by increases in tumor growth delay. Treatment of the tumor-bearing animals with paclitaxel or carboplatin followed by treatment with 317615 x 2HCl resulted in a 2.5- to 3.0-fold increase in tumor growth delay compared with the standard chemotherapeutic agents alone.

CONCLUSIONS:

317615 x 2HCl represents a new approach to antiangiogenic therapy in cancer-blocking multiple growth factor signaling pathways in endothelial cells with a single agent. 317615 x HCl is in early clinical testing.

• Authors: Beverly A Teicher, Enrique Alvarez, Krishna Menon, Michail A Esterman, Eileen Considine, Chuan Shih, Margaret M Faul
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 49 Issue 1 Pg. 69-77 (Jan 2002) ISSN: 0344-5704 [Print] Germany
• PMID: 11855754 (Publication Type: Journal Article)

Chemical References

• 317615 x 2HCl
• Angiogenesis Inducing Agents
• Angiogenesis Inhibitors
• Antineoplastic Agents, Alkylating
• Basic Helix-Loop-Helix Transcription Factors
• Endothelial Growth Factors
• Enzyme Inhibitors
• Isoenzymes
• Lymphokines
• Organic Chemicals
• Trans-Activators
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• endothelial PAS domain-containing protein 1
• Protein Kinase C
• Protein Kinase C beta

Topics

• Angiogenesis Inducing Agents (pharmacology)
• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antineoplastic Agents, Alkylating (pharmacology)
• Aorta, Thoracic (cytology, drug effects)
• Basic Helix-Loop-Helix Transcription Factors
• Carcinoma, Small Cell (blood supply, pathology)
• Cornea (blood supply, pathology)
• Endothelial Growth Factors (pharmacology)
• Endothelium, Vascular (cytology, drug effects)
• Enzyme Inhibitors (pharmacology)
• Female
• Humans
• Isoenzymes (antagonists & inhibitors, metabolism)
• Lung Neoplasms (blood supply, pathology)
• Lymphokines (pharmacology)
• Male
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neovascularization, Pathologic (prevention & control)
• Organic Chemicals
• Protein Kinase C (antagonists & inhibitors)
• Protein Kinase C beta
• Rats
• Rats, Inbred F344
• Trans-Activators (pharmacology)
• Tumor Cells, Cultured
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors