Antiangiogenic and antitumor effects of a protein kinase Cbeta inhibitor in human T98G glioblastoma multiforme xenografts.
Although rare, the morbidity and mortality from brain tumors are significant. Chemotherapy has made only a small impact on these tumors. The human T98G glioblastoma multiforme cell line was used as a brain tumor model. The protein kinase Cbeta inhibitor 317615 x 2HCl was not highly cytotoxic toward T98G cells in culture and was additive in cytotoxicity with carmustine (BCNU). When nude mice bearing s.c. T98G tumors were treated with 317615 x 2HCl p.o. twice daily on days 14-30 after tumor cell implantation, the number of intratumoral vessels stained by CD31 was decreased to 37% of control, and the number of intratumoral vessels stained by CD105 was decreased to 50% of control. The compound 317615 x 2HCl was an active antitumor agent against s.c. growing T98G xenografts. A treatment regimen administering 317615 x 2HCl before, during, and after BCNU was compared with a treatment regimen administering 317615 x 2HCl sequentially after BCNU. In the tumor growth delay determination of the s.c. tumor, the sequential treatment regimen was more effective than the simultaneous treatment regimen. However, when the same treatments were administered to animals bearing intracranial T98G tumors, the survival of animals receiving the simultaneous treatment regimen increased from 41 days for those treated with BCNU alone to 102 days for animals treated with the combination, whereas animals receiving the sequential treatment regimen survived 74 days. Treatment with the protein kinase Cbeta inhibitor decreased T98G glioblastoma multiforme angiogenesis and improved treatment outcome with BCNU.
Teicher
B A
BA
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. TEICHER_BEVERLY_A@Lilly.com
Menon
K
K
Alvarez
E
E
Galbreath
E
E
Shih
C
C
Faul
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D002330:Carmustine / Q000627:therapeutic use; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy*; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D009930:Organic Chemicals; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D013997:Time Factors; D014407:Tumor Cells, Cultured
C436248:317615 x 2HCl; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009930:Organic Chemicals; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D002330:Carmustine