Antiangiogenic and antitumor effects of a protein kinase C beta inhibitor in human hepatocellular and gastric cancer xenografts.
Hepatocellular carcinoma and gastric cancer are the most prevalent tumors worldwide. Hep3B hepatocellular carcinoma and HS746T gastric cancer were used as models for these diseases in culture and in vivo. The PKC beta inhibitor 317615.2HCl was not very cytotoxic toward HS746T or Hep3B cells in culture and was, in the main, additive in cytotoxicity with cisplatin, 5-fluorouracil and gemcitabine when cell in monolayer were exposed to these agents in combination with 317615.2HCl. Treatment of nude mice bearing HS746T or Hep3B xenografts with 317615.2HCl orally twice daily resulted in a small decreased in CD31-stainable intratumoral vessels in the HS746T tumors and 60% decrease in CD31-stainable vessels in the Hep3B tumors. Somewhat larger decreases were observed in the vessel stained with CD105. As a single agent 317615.2HCl produced tumor growth delays between 6.5 and 15 days in the HS746T xenograft and between 5 and 25 days in the Hep3B xenograft over the dosage range (3 to 30 mg/kg). Sequential and simultaneous combinations with 317615.2HCl and 5-fluorouracil and gemcitabine resulted in increases in tumor growth delay on both schedules. Gemcitabine produced a 15-day tumor growth delay of the HS746T gastric carcinoma that was increased to 40 days when combined simultaneously with 317615.2HCl and to 30 days with the sequential treatment regimen. 5-Fluorouracil produced a 9-day tumor growth delay of the Hep3B hepatocellular carcinoma that increased to 31 days by simultaneous treatment with 317615.2HCl and to 43 days with the sequential treatment regimen. Treatment with the protein kinase C beta inhibitor 317615.2HCl decreased HS746T and Hep3B angiogenesis and improved treatment outcome with 5-fluorouracil and gemcitabine.
Teicher
B A
BA
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. TEICHER BEVERLY A@Lilly.com
Menon
K
K
Alvarez
E
E
Liu
P
P
Shih
C
C
Faul
M M
MM
D000368:Aged; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002648:Child; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000473:pathology; D009930:Organic Chemicals; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
C436248:317615 x 2HCl; D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009930:Organic Chemicals; D003841:Deoxycytidine; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D005472:Fluorouracil; D000093542:Gemcitabine