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Titolo:
NITRO REDUCTION AS AN ELECTRONIC SWITCH FOR BIOREDUCTIVE DRUG ACTIVATION
Autore:
SIIM BG; DENNY WA; WILSON WR;
Indirizzi:
UNIV AUCKLAND,DEPT PATHOL,SECT ONCOL,PRIVATE BAG 92019 AUCKLAND 1 NEWZEALAND UNIV AUCKLAND,CANC SOC RES LAB AUCKLAND 1 NEW ZEALAND
Titolo Testata:
Oncology research
fascicolo: 6-7, volume: 9, anno: 1997,
pagine: 357 - 369
SICI:
0965-0407(1997)9:6-7<357:NRAAES>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
SELECTIVE ANTITUMOR AGENTS; ENZYME PRODRUG THERAPY; ESCHERICHIA-COLI NITROREDUCTASE; MUSTARD QUATERNARY-SALTS; SQUAMOUS-CELL CARCINOMA; HAMSTER OVARY CELLS; FLAVONE ACETIC-ACID; NITRACRINE N-OXIDE; ALKYLATING-AGENTS; CANCER-THERAPY;
Keywords:
HYPOXIA; NITRO REDUCTION; BIOREDUCTIVE DRUGS; NITROGEN MUSTARD; ADEPT; GDEPT;
Tipo documento:
Article
Natura:
Periodico
Citazioni:
86
Recensione:
Indirizzi per estratti:
Citazione:
B.G. Siim et al., "NITRO REDUCTION AS AN ELECTRONIC SWITCH FOR BIOREDUCTIVE DRUG ACTIVATION", Oncology research, 9(6-7), 1997, pp. 357-369

Abstract

It is well known that the reduction of aromatic nitro groups can giverise to toxic species, and that net nitro reduction by one-electron reductases can usually be inhibited by oxygen. There has been much interest in utilizing this biotransformation to activate drugs in hypoxic regions of tumors, but no clinically useful compound has yet resulted. Nitroreductive activation of prodrugs by oxygen-insensitive (and oxygen-sensitive) reductases is also of current interest because of new methods for introducing specific nitroreductases into tumors (e.g., as antibody-enzyme conjugates or by gene therapy). In most of the compounds investigated previously, cytotoxicity appears to be due to reactive nitroso or hydroxylamine reduction products arising from the nitro group itself. It is argued that there is greater scope for designing potent and selective nitro compounds by using the nitro group as an electronic switch to activate a latent reactive moiety elsewhere in the molecule. Examples of this approach include the nitro(hetero)aromatic mustards (e.g., SN 23816, NSC 646394) in which the nitro group controls the reactivity of a nitrogen mustard to which it is directly conjugated,and the nitro(hetero)aromatic methylquaternary (NMQ) mustards (e.g., SN 25341, NSC 658926) in which reduction of the nitro group triggers fragmentation of the molecule to release a reactive aliphatic nitrogen mustard. Many of these compounds show very high selectivity for hypoxic cells in culture. Some are also active against hypoxic cells in tumors, and provide large tumor growth delays when combined with tumor blood flow inhibitors such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA). These prodrug designs also have potential for releasing effecters other than nitrogen mustards, which opens up many possibilities for useof nitro compounds as tumor-selective prodrugs.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/11/20 alle ore 00:51:12