Antiangiogenic and antitumor effects of a protein kinase Cbeta inhibitor in human breast cancer and ovarian cancer xenografts.
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.
Teicher
Beverly A
BA
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. teicher_beverly_a@lilly.com
Menon
Krishna
K
Alvarez
Enrique
E
Shih
Chuan
C
Faul
Margaret M
MM
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology* / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000532:radiotherapy; D016190:Carboplatin / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D009930:Organic Chemicals; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000532:radiotherapy; D017239:Paclitaxel / Q000627:therapeutic use; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D012039:Regional Blood Flow / Q000187:drug effects; D014183:Transplantation, Heterologous
C436248:317615 x 2HCl; D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D009930:Organic Chemicals; D016190:Carboplatin; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D017239:Paclitaxel