Efficacy of an angiogenesis inhibitor, TNP-470, in xenotransplanted human colorectal cancer with high metastatic potential.
BACKGROUND
The summation of gene mutations increases the metastatic potential of colorectal cancer. The genetic characterization and hepatic metastatic potential of five xenotransplanted human colon carcinoma strains were investigated. Furthermore, the therapeutic effect of the angiogenesis inhibitor, TNP-470, was evaluated.


METHODS
The correlation between gene mutation and rate of hepatic metastases of five colon cancer strains transplanted orthotopically or subcutaneously was evaluated. The strain with the highest hepatic metastatic rate from orthotopical tumors, TK-4, was used in the experiment with TNP-470 treatment. Mice were given tumor transplants orthotopically or subcutaneously followed by 30 mg/kg of TNP-470 on alternate days from Day 10 or Day 21 after transplantation, respectively.


RESULTS
The rate of hepatic metastases from orthotopically transplanted tumors of 5 strains was 38 to 79%. Interestingly, TK-4 with K-ras and p53 mutations and overexpression of p53 protein induced hepatic metastases from both orthotopical (79%) and subcutaneous tumors (44%). Although TNP-470 only significantly inhibited subcutaneous tumor growth, its antimetastatic effect was significantly demonstrated on the hepatic metastases of both orthotopical and subcutaneous tumors.


CONCLUSIONS
p53 mutation is thought to enhance angiogenesis, favoring the growth of the hepatic metastases. TNP-470 proved the excellent antimetastatic effect of TK-4 on hepatic metastases. TK-4 has the highest metastatic potential and p53 mutation. An antiproliferative effect was observed on the rapidly growing primary tumors in which angiogenesis may be dominant.
Konno
H
H
Second Department of Surgery, Hamamatsu University, School of Medicine, Japan.
Tanaka
T
T
Kanai
T
T
Maruyama
K
K
Nakamura
S
S
Baba
S
S
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000235:genetics; D003510:Cyclohexanes; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol