Equivalent effect of DNA damage-induced apoptotic cell death or long-term cell cycle arrest on colon carcinoma cell proliferation and tumour growth.
Knowledge of the type of biological reaction to chemotherapy is a prerequisite for its rational enhancement. We previously showed that irinotecan-induced DNA damage triggers in the HCT116p53(wt) colon carcinoma cell line a long-term cell cycle arrest and in HCT116p53(-/-) cells apoptosis (Magrini et al., 2002). To compare the contribution of long-term cell cycle arrest and that of apoptosis to inhibition of cell proliferation after irinotecan-induced DNA damage, we used this isogenic system as well as the cell lines LS174T (p53(wt)) and HT-29 (p53(mut)). Both p53(wt) cell lines responded to damage by undergoing a long-term tetraploid G1 arrest, whereas the p53(mut) cell lines underwent apoptosis. Cell cycle arrest as well as apoptosis caused a similar delay in cell proliferation. Irinotecan treatment also induced in mouse tumours derived from the p53(wt) cell lines a tetraploid G1 arrest and in those derived from the p53-deficient cell lines a transient G2/M arrest and apoptosis. The delay of tumour growth was in the same range in both groups, that is, arrest- and apoptosis-mediated tumour growth inhibition was comparable. In conclusion, cell cycle arrest as well as apoptosis may be equipotent mechanisms mediating the chemotherapeutic effects of irinotecan.
Bhonde
M R
MR
Department of Gastroenterology, Charité-Universitaetsmedizin Berlin, Germany.
Hanski
M-L
ML
Notter
M
M
Gillissen
B F
BF
Daniel
P T
PT
Zeitz
M
M
Hanski
C
C
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002453:Cell Cycle; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004249:DNA Damage; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D009336:Necrosis; D011003:Ploidies; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D059004:Topoisomerase I Inhibitors; D016159:Tumor Suppressor Protein p53; D000077146:Irinotecan; D002166:Camptothecin