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Titolo:
IN-VITRO INACTIVATION OF HUMAN O-6-ALKYLGUANINE DNA ALKYLTRANSFERASE BY ANTITUMOR TRIAZENE COMPOUNDS
Autore:
LACAL PM; DATRI S; ORLANDO L; BONMASSAR E; GRAZIANI G;
Indirizzi:
IRCCS,IDI,VIA MONTI DI CRETA 104 I-00167 ROME ITALY UNIV ROMA TOR VERGATA,DEPT EXPT MED & BIOCHEM SCI I-00173 ROME ITALY
Titolo Testata:
The Journal of pharmacology and experimental therapeutics
fascicolo: 1, volume: 279, anno: 1996,
pagine: 416 - 422
SICI:
0022-3565(1996)279:1<416:IIOHOD>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN O6-METHYLGUANINE-DNA METHYLTRANSFERASE; ADVANCED MALIGNANT-MELANOMA; TUMOR INHIBITORY TRIAZENES; PHASE-I TRIAL; HUMAN-CELLS; ALKYLATING-AGENTS; ESCHERICHIA-COLI; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; INTRACELLULAR-LOCALIZATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
58
Recensione:
Indirizzi per estratti:
Citazione:
P.M. Lacal et al., "IN-VITRO INACTIVATION OF HUMAN O-6-ALKYLGUANINE DNA ALKYLTRANSFERASE BY ANTITUMOR TRIAZENE COMPOUNDS", The Journal of pharmacology and experimental therapeutics, 279(1), 1996, pp. 416-422

Abstract

The cytotoxic and mutagenic properties of antitumor triazene compounds (TZC) have been mainly attributed to their ability to form DNA adducts at the O-6 position of guanine. Repair of these lesions is mediatedby O-6-alkylguanine DNA alkyltransferase (OGAT) in an autoinactivating reaction. Therefore when lesion repair has occurred, cells are depleted of OGAT until synthesis of new enzyme molecules takes place. In this study, we have evaluated the ability of DNA alkylated by different TZC to deplete COAT activity. Moreover, we have also investigated whether these compounds might inactivate the OGAT enzyme by a direct reaction with the protein. Human OGAT protein was partially purified from insect cells infected with a recombinant baculovirus containing the human OGAT coding sequences. Thereafter human OGAT protein was exposed directly to TZC or to TZC-alkylated DNA. Among the TZC tested, p-(3-methyl-1-triazeno)benzoic acid was the most effective COAT inactivator by direct interaction with the protein. Moreover DNA substrates treated with methylating TZC, such as temozolomide or p-(3-methyl-1-triazeno)benzoic acid, were more effective in depleting the repair enzyme, compared to DNA pretreated with the chloroethylating TZC mitozolomide. In conclusion, our results show that TZC inactivate in vitro COAT activity by either direct or indirect mechanisms. Therefore TZC are good candidates for 1) increasing their own cytotoxicity, if used according to appropriate dose and treatment schedules and 2) reversing tumor cell resistance to O-6-guanine alkylating agents.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/10/20 alle ore 05:55:32