Liver metastasis models of colon cancer for evaluation of drug efficacy using NOD/Shi-scid IL2Rgammanull (NOG) mice.
To examine the drug efficacy of a novel farnesyltransferase inhibitor (FTI), CH4512600, in vivo, we developed a reliable liver metastasis model of human colon cancer using NOD/Shi-scid IL2Rgamma(null) (NOG) mice. Eleven human colon cancer cell lines were examined for their ability to form diverse metastatic foci in the livers of NOG mice. When inoculated with 10(4) COLO320DM, HCT 116, HT-29, WiDr, LoVo and LS174T cells, liver metastasis was evident in 100% (6/6), 100% (6/6), 88.9% (8/9), 87.5% (7/8), 83.3% (5/6) and 50.0% (3/6) of the NOG mice, respectively. CaCo2, COLO201, LS123, SW48 and SW1417 showed no metastasis when seeded at 10(4) cells even in NOG mice. The mRNA expression levels and genetic mutations of N, H and K-RAS genes, which directly affect the levels of cellular RAS protein that would be molecular target for FTI, were also examined in these six metastatic human colon cancer cell lines for molecular biological and genotypic characteristics. Only three cell lines had a point mutation in the RAS oncogene. LS174T cell line had a point mutation of the K-RAS gene at codon 12 (gly12 --> asp; G12D), and HCT 116 and LoVo cell lines had a point mutation of the K-RAS gene at codon 13 (gly13 --> asp; G13D). Relative gene expression levels of N, H and K-RAS genes in the HCT 116 cell line were 2.6-5.0-fold lower than that of LS174T and LoVo cell lines. We selected HCT 116 cell line from our liver metastasis model for evaluation of FTI CH4512600 efficacy in vivo. Using the NOG mouse liver metastasis model, we demonstrated the effectiveness of FTI CH4512600 to suppress tumor growth in vivo and to prolong mouse survival significantly from 36.9+/-2.9 to 50.3+/-9.4 days.
Hamada
Kenji
K
Biomedical Research Department, Central Institute for Experimental Animals, Miyamae, Kawasaki, Kanagawa 216-0001, Japan.
Monnai
Makoto
M
Kawai
Kenji
K
Nishime
Chiyoko
C
Kito
Chika
C
Miyazaki
Noriyuki
N
Ohnishi
Yasuyuki
Y
Nakamura
Masato
M
Suemizu
Hiroshi
H
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001572:Benzofurans / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000556:secondary*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015375:Receptors, Interleukin-2 / Q000235:genetics; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D000970:Antineoplastic Agents; D001572:Benzofurans; C527366:CH 4512600; D007093:Imidazoles; D015375:Receptors, Interleukin-2; D042461:Vascular Endothelial Growth Factor A; D051231:Farnesyltranstransferase