The resistance of advanced
colorectal cancers to
therapy is often related to mutations in the p53 tumor suppressor gene. Because
somatostatin (SRIF) receptors (ssts) are present in
colorectal carcinomas, the treatment with targeted cytotoxic SRIF analogue
AN-238, consisting of
2-pyrrolinodoxorubicin (AN-201) linked to octapeptide SRIF carrier
RC-121, may overcome this resistance by producing a higher concentration of the
cytotoxic agent in the
tumors. Four
colon cancer cell lines, HCT-116 and LoVo expressing wild-type p53, and HCT-15 and HT-29 with mutated p53, were investigated. HCT-116, HCT-15, and HT-29, but not LoVo possess functional ssts. We analyzed changes in p53, p21, and
proliferating cell nuclear antigen (
PCNA) concentrations in these cells in vitro by immunoblotting after exposure to
AN-238, its radical
AN-201, or
doxorubicin (DOX). Equitoxic doses of
AN-238,
AN-201, or DOX affected p53, p21, and
PCNA differently. Analysis of the p21:p53 ratios revealed that DOX increased p53 levels, but most of p53 was mutated and inactive, whereas
AN-238 produced smaller changes in p53 concentrations but enhanced its activity. In HCT-15 cells,
PCNA:p21 ratios, which are indicators of proliferation and repair processes, remained unchanged after exposure to
AN-238 but were increased by DOX. In vivo studies in nude mice demonstrated that
AN-238,
AN-201, and DOX were equally effective on HCT-116
tumors that express wild-type p53. However,
AN-238 also inhibited the growth of HCT-15 and HT-29
cancers that express mutant p53, whereas
AN-201 and DOX showed no effect. None of the compounds could suppress the proliferation of LoVo
tumors that lack functional ssts. In conclusion, cytotoxic SRIF analogue
AN-238 inhibits the growth of experimental
colon cancers that express ssts, regardless of their p53 status.