st-1968 and Ovarian-Neoplasms

DNA damage response and checkpoint activation are expected to influence the sensitivity to DNA-damaging agents. This study was designed to investigate the DNA damage response to the novel camptothecin, ST1968, in two tumor cell lines with a different biological background (A2780 and KB), which underwent distinct cell cycle perturbations and cell death modalities. Following treatment with the camptothecin or ionizing radiation, both inducing double-strand DNA breaks, the ovarian carcinoma A2780 cells exhibited activation of the ATM-Chk2 pathway and early induction of apoptosis. In contrast, the squamous carcinoma KB cells exhibited activation of ATR-Chk1 pathway, a persistent G(2)/M-phase arrest, cellular senescence, mitotic catastrophe and delayed apoptosis, suggesting a defective ATM pathway. The cellular response to UV-induced DNA damage, which activates ATR-Chk1 pathway, was similar in the two cell lines exhibiting early apoptosis induction. Inhibition of ATM in A2780 cells, resulting in reduced phosphorylation of Chk2, enhanced ST1968-induced apoptosis, but had no effect in KB cells. The susceptibility to camptothecin-induced apoptosis of A2780 cells was likely p53-dependent but not related to the activation of the ATM pathway. In contrast, the inhibition of Chk1 enhanced apoptosis response in KB cell but not in A2780. Thus, depending on the biological context, the camptothecin activated ATM-Chk2 or ATR-Chk1 pathways, both having a protective role. In conclusion, our results are consistent with the interpretation that the modality of cell death response is not the critical determinant of sensitivity to camptothecins, and support the interest of inhibition of checkpoint kinases to improve the efficacy of camptothecins.

Topics: Ataxia Telangiectasia Mutated Proteins; Camptothecin; Carcinoma, Squamous Cell; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; DNA Damage; DNA-Binding Proteins; Female; Humans; Infrared Rays; Ovarian Neoplasms; Protein Serine-Threonine Kinases; Tumor Suppressor Proteins; Ultraviolet Rays

ST1968, a novel hydrophilic camptothecin analogue of the 7-oxyiminomethyl series, is characterised by the formation of stable DNA-topoisomerase I cleavable complex and by a promising profile of antitumour activity. The present study was designed to extend preclinical evaluation of the novel camptothecin in human squamous cell carcinoma (SCC) models. ST1968 exhibited an impressive activity with a high cure rate in SCC models. ST1968 produced 100% of complete response without evidence of regrowth in tumours characterised by susceptibility to drug-induced apoptosis (FaDu, A431 and A2780). In contrast to irinotecan, ST1968 still showed an excellent, persisting activity in models less susceptible to apoptosis induction (KB, Caski and SiHa), in which drug treatment elicited a persistent DNA damage response, as documented by phosphorylation of p53, RPA-2 and histone H2AX, resulting in delayed apoptosis and senescence. This behaviour was associated with a marked cellular/tumour drug accumulation. In conclusion, ST1968 exhibited an outstanding antitumour activity superior to that of irinotecan against SCC. A high intracellular accumulation, resulting in fast apoptosis or DNA damage persistence, appeared to be a critical determinant of SCC sensitivity to ST1968.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Camptothecin; Carcinoma, Squamous Cell; Caspase 3; DNA Damage; Drug Evaluation; Female; Humans; Irinotecan; Male; Mice; Mice, Nude; Neoplasm Transplantation; Ovarian Neoplasms; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Prostatic Neoplasms; Transplantation, Heterologous; Tumor Cells, Cultured