Intracellular accumulation and DNA damage persistence as determinants of human squamous cell carcinoma hypersensitivity to the novel camptothecin ST1968
| Autor: | Loredana Vesci, Concetta Aulicino, Rosanna Foderà, Claudio Pisano, Michelandrea De Cesare, Federica Bucci, Franco Zunino, Valentina Benedetti, Sergio Penco, Paolo Carminati, Valentina Zuco |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Cancer Research Programmed cell death DNA damage Transplantation Heterologous Poly (ADP-Ribose) Polymerase-1 Mice Nude Apoptosis Camptothecin Analogue Irinotecan Mice medicine Tumor Cells Cultured Animals Humans neoplasms Ovarian Neoplasms biology Caspase 3 Topoisomerase Prostatic Neoplasms Antineoplastic Agents Phytogenic Oncology Biochemistry Epidermoid carcinoma biology.protein Cancer research Carcinoma Squamous Cell Drug Evaluation Camptothecin Female Poly(ADP-ribose) Polymerases Neoplasm Transplantation medicine.drug DNA Damage |
| Zdroj: | European journal of cancer (Oxford, England : 1990). 44(9) |
| ISSN: | 0959-8049 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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