Antiangiogenic and antitumor effects of a protein kinase Cbeta inhibitor in human HT-29 colon carcinoma and human CaKi1 renal cell carcinoma xenografts.
The compound 317615 x 2HCl, a selective protein kinase Cbeta inhibitor, was not very cytotoxic toward human CaKi1 renal cell carcinoma cells or human HT-29 colon carcinoma cells in monolayer culture. Isobologram analysis was used to determine additivity or synergy of the combination regimens. Exposure of CaKi1 cells to 317615 x 2HCl (10 or 100 mM) along with gemcitabine or 5-fluorouracil for 24 hours resulted in cytotoxicity that appeared to be less-than-additive to additive for the two agents. Exposure of HT-29 cells to gemcitabine along with 317615 x 2HCl (10 mM or 100 mM) resulted in a synergistic cytotoxicity while combinations with 5-fluorouracil resulted in additive to greater-than-additive cytotoxicity for the agents. After treatment of CaKi1 or HT-29 xenograft-bearing mice with 317615 x 2HCl, immunohistochemical staining for expression of endothelial specific markers, either CD31 or CD105, was used to quantify the number of intratumoral vessels in the samples. CaKi1 tumor angiogenesis was very responsive to treatment with 317615 x 2HCl such that the number of intratumoral vessels stained by CD31 or CD105 was decreased to 20% of the control. The HT-29 colon carcinoma angiogenesis was also responsive to 317615 x 2HCl, such that the number of intratumoral vessels stained by CD31 or CD105 was decreased to 40% to 50% of the controL 5-fluorouracil, cisplatin or fractionated radiation therapy was combined with treatment with 317615 x 2HCl in the simultaneous combination treatment regimen in animals bearing HT-29 colon carcinoma xenografts. The resulting tumor growth delays indicated that administration of 317615 x 2HCl increased the effects of the cytotoxic therapy. Both a simultaneous or an overlapping treatment regimen and a sequential treatment regimen were used to assess 317615 x 2HCl alone and along with fractionated radiation therapy or gemcitabine against the human CaKi1 renal cell carcinoma xenograft. The CaKi1 tumor was quite sensitive to fractionated radiation therapy and to gemcitabine and, although 317615 x 2HCl was an effective single agent in this tumor, the combination regimens did not reach additivity for the combination regimens in vivo. 317615 x 2HCl is in early clinical testing.
Teicher
B A
BA
Lilly Research Laboratories, Indianapolis, IN 46285, USA. TEICHER_BEVERLY_A@Lilly.com
Menon
K
K
Alvarez
E
E
Galbreath
E
E
Shih
C
C
Faul
M M
MM
D000328:Adult; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D019073:HT29 Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009930:Organic Chemicals; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
C436248:317615 x 2HCl; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009930:Organic Chemicals; D003841:Deoxycytidine; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D002945:Cisplatin; D005472:Fluorouracil; D000093542:Gemcitabine