title: In vivo toxicity study of N-1-sulfonylcytosine derivatives and their mechanisms of action in cervical carcinoma cell line.
abstract: New N-1-sulfonylpyrimidines showed potent growth inhibitory activity against human and mouse tumour cells of different origin. 1-(p-toluenesulfonyl)cytosine (TsC) and 1-(p-toluenesulfonyl)cytosine hydrochloride (TsC × HCl) inhibited the growth of human cervical carcinoma cells (HeLa), and had no significant cytotoxic effects on normal human foreskin fibroblasts (BJ). TsC and TsC × HCl interfered with the HeLa cell cycle progression bringing about the accumulation of G1 phase cells and the induction of apoptosis. Antiproliferative effects of TsC and TsC × HCl were additionally confirmed by investigating de novo synthesis of RNA, DNA and proteins in HeLa cells. Monitoring gene expression using DNA Chip Analysis and quantitative PCR showed that TsC × HCl affects the expression of several cell-cycle regulating genes implying that cell cycle arrest and DNA damage-induced apoptosis might account for the observed cellular effects. In vivo experiments revealed low toxicity of TsC × HCl, as demonstrated by unaltered haematological and metabolic blood parameters. In conclusion, potent antitumour efficacy and low toxicity of new compounds in comparison with the common chemotherapy drug 5-FU make them promising anticancer agents. Additional pre-clinical and clinical studies are warranted to illuminate the mode of action of these newly synthesized compounds in vivo, which would lay the groundwork for their further optimization.
authors.affiliation: German Heart Center, Technical University Munich, Lazarettstraße 36, 80636, Munich, Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Kašnar-Šamprec
authors.forename: Ivana
authors.initials: I
authors.lastname: Ratkaj
authors.forename: Katarina
authors.initials: K
authors.lastname: Mišković
authors.forename: Marina
authors.initials: M
authors.lastname: Pavlak
authors.forename: Mirela
authors.initials: M
authors.lastname: Baus-Lončar
authors.forename: Sandra
authors.initials: S
authors.lastname: Kraljević Pavelić
authors.forename: Ljubica
authors.initials: L
authors.lastname: Glavaš-Obrovac
authors.forename: Biserka
authors.initials: B
authors.lastname: Žinić
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity; D004249:DNA Damage; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D052816:Foreskin / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006403:Hematologic Tests; D006801:Humans; D008297:Male; D017208:Rats, Wistar; D002583:Uterine Cervical Neoplasms / Q000097:blood / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003596:Cytosine