N-(4-iodophenyl)-N'-(2-chloroethyl)urea as a microtubule disrupter: in vitro and in vivo profiling of antitumoral activity on CT-26 murine colon carcinoma cell line cultured and grafted to mice.
The antitumoral profile of the microtubule disrupter N-(4-iodophenyl)-N'-(2-chloroethyl)urea (ICEU) was characterised in vitro and in vivo using the CT-26 colon carcinoma cell line, on the basis of the drug uptake by the cells, the modifications of cell cycle, and beta-tubulin and lipid membrane profiles. N-(4-iodophenyl)-N'-(2-chloroethyl)urea exhibited a rapid and dose-dependent uptake by CT-26 cells suggesting its passive diffusion through the membranes. Intraperitoneally injected ICEU biodistributed into the grafted CT-26 tumour, resulting thus in a significant tumour growth inhibition (TGI). N-(4-iodophenyl)-N'-(2-chloroethyl)urea was also observed to accumulate within colon tissue. Tumour growth inhibition was associated with a slight increase in the number of G2 tetraploid tumour cells in vivo, whereas G2 blockage was more obvious in vitro. The phenotype of beta-tubulin alkylation that was clearly demonstrated in vitro was undetectable in vivo. Nuclear magnetic resonance analysis showed that cells blocked in G2 phase underwent apoptosis, as confirmed by an increase in the methylene group resonance of mobile lipids, parallel to sub-G1 accumulation of the cells. In vivo, a decrease of the signals of both the phospholipid precursors and the products of membrane degradation occurred concomitantly with TGI. This multi-analysis established, at least partly, the ICEU activity profile, in vitro and in vivo, providing additional data in favour of ICEU as a tubulin-interacting drug accumulating within the intestinal tract. This may provide a starting point for researches for future efficacious tubulin-interacting drugs for the treatment of colorectal cancers.
Borel
M
M
INSERM, U484, Clermont-Ferrand, F-63005 France.
Degoul
F
F
Communal
Y
Y
Mounetou
E
E
Bouchon
B
B
C-Gaudreault
R
R
Madelmont
J C
JC
Miot-Noirault
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D002277:Carcinoma / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D004353:Drug Evaluation, Preclinical; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008870:Microtubules / Q000187:drug effects*; D008954:Models, Biological; D009368:Neoplasm Transplantation / Q000473:pathology; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D010743:Phospholipids / Q000737:chemistry; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000493:pharmacokinetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D010743:Phospholipids; D014404:Tubulin; D050257:Tubulin Modulators