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Titolo:
Tirapazamine: a bioreductive anticancer drug that exploits tumour hypoxia
Autore:
Denny, WA; Wilson, WR;
Indirizzi:
Univ Auckland, Fac Med & Hlth Sci, Auckland Canc Soc Res Ctr, Auckland 1000, New Zealand Univ Auckland Auckland New Zealand 1000 Ctr, Auckland 1000, New Zealand
Titolo Testata:
EXPERT OPINION ON INVESTIGATIONAL DRUGS
fascicolo: 12, volume: 9, anno: 2000,
pagine: 2889 - 2901
SICI:
1354-3784(200012)9:12<2889:TABADT>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
CELL LUNG-CANCER; FLAVONE ACETIC-ACID; PHASE-I TRIAL; CYTOTOXIC AGENT TIRAPAZAMINE; ADVANCED MALIGNANT-MELANOMA; GUIDED DOSE-ESCALATION; HAMSTER OVARY CELLS; EVERY 3 WEEKS; FRACTIONATED-IRRADIATION; 3-AMINO-1,2,4-BENZOTRIAZINE 1,4-DIOXIDE;
Keywords:
cytochrome P450 reductase; DNA break; free radical; hypoxia-selective cytotoxin; tirapazamine;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
112
Recensione:
Indirizzi per estratti:
Indirizzo: Denny, WA Univ Auckland, Fac Med & Hlth Sci, Auckland Canc Soc Res Ctr, Private Bag 92019, Auckland 1000, New Zealand Univ Auckland Private Bag 92019Auckland New Zealand 1000 aland
Citazione:
W.A. Denny e W.R. Wilson, "Tirapazamine: a bioreductive anticancer drug that exploits tumour hypoxia", EXPERT OP I, 9(12), 2000, pp. 2889-2901

Abstract

Tirapazamine is the second clinical anticancer drug (after porfiromycin) that functions primarily as a hypoxia-selective cytotoxin. Hypoxic cells in tumours are relatively resistant to radiotherapy and to some forms of chemotherapy and are also biologically aggressive, thus representing an important target population in oncology. Tirapazamine undergoes metabolism by reductases to form a transient oxidising radical that can be efficiently scavenged by molecular oxygen in normal tissues to re-form the parent compound. Inthe absence of oxygen, the oxidising radical abstracts a proton from DNA to form DNA radicals, largely at C4' on the ribose ring. Tirapazamine can also oxidise such DNA radicals to cytotoxic DNA strand breaks. It therefore shows substantial selective cytotoxicity for anoxic cells in culture (typically similar to 100-fold more potent than under oxic conditions) and for thehypoxic subfraction of cells in tumours. Preclinical studies showed enhanced activity of combinations of tirapazamine with radiation (to kill oxygenated cells) and with conventional cytotoxics, especially cisplatin (probablythrough inhibition of repair of cisplatin DNA cross-links in hypoxic cells). Phase II and III clinical studies of tirapazamine and cisplatin in malignant melanoma and non-small cell lung cancer suggest that the combination is more active than cisplatin alone and preliminary results with advanced squamous cell carcinomas of the head and neck indicate that tirapazamine may enhance the activity of cisplatin with fractionated radiotherapy.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 31/10/20 alle ore 20:07:26