Intracellular accumulation and DNA damage persistence as determinants of human squamous cell carcinoma hypersensitivity to the novel camptothecin ST1968.
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.
Pisano
Claudio
C
Sigma-tau S.p.A., Pomezia, Rome, Italy. claudio.pisano@sigma-tau.it
Zuco
Valentina
V
De Cesare
Michelandrea
M
Benedetti
Valentina
V
Vesci
Loredana
L
Foderà
Rosanna
R
Bucci
Federica
F
Aulicino
Concetta
C
Penco
Sergio
S
Carminati
Paolo
P
Zunino
Franco
F
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D053148:Caspase 3 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; C531200:namitecan; D002166:Camptothecin