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Titolo:
6-AMINONICOTINAMIDE SENSITIZES HUMAN TUMOR-CELL LINES TO CISPLATIN
Autore:
BUDIHARDJO II; WALKER DL; SVINGEN PA; BUCKWALTER CA; DESNOYERS S; ECKDAHL S; SHAH GM; POIRIER GG; REID JM; AMES MM; KAUFMANN SH;
Indirizzi:
MAYO CLIN & MAYO FDN,DIV ONCOL RES,200 1ST ST SW ROCHESTER MN 55905 MAYO CLIN & MAYO FDN,DIV ONCOL RES ROCHESTER MN 55905 MAYO CLIN & MAYO FDN,DEPT LAB MED ROCHESTER MN 55905 MAYO CLIN & MAYO FDN,MAYO MED SCH,DEPT PHARMACOL ROCHESTER MN 55905 CHU LAVAL,RES CTR,METAB GRP,UNIT HLTH & ENVIRONM QUEBEC CITY PQ G1V 4G2 CANADA UNIV LAVAL QUEBEC CITY PQ G1V 4G2 CANADA
Titolo Testata:
Clinical cancer research
fascicolo: 1, volume: 4, anno: 1998,
pagine: 117 - 130
SICI:
1078-0432(1998)4:1<117:6SHTLT>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
AMINO-ACID-TRANSPORT; HUMAN POLY(ADP-RIBOSE) POLYMERASE; ANTISENSE RNA EXPRESSION; GENE-SPECIFIC REPAIR; BIOCHEMICAL MODULATION; ANTICANCER DRUGS; OVARIAN-CANCER; IN-VITRO; ACQUIRED-RESISTANCE; ANTITUMOR-ACTIVITY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
85
Recensione:
Indirizzi per estratti:
Citazione:
I.I. Budihardjo et al., "6-AMINONICOTINAMIDE SENSITIZES HUMAN TUMOR-CELL LINES TO CISPLATIN", Clinical cancer research, 4(1), 1998, pp. 117-130

Abstract

The nicotinamide analogue 6-aminonicotinamide (6AN) is presently undergoing evaluation as a potential modulator of the action of various antineoplastic treatments, Most previous studies of this agent have focused on a three-drug regimen of chemical modulators that includes 6AN, In the present study, the effect of single-agent 6AN on the efficacy of selected antineoplastic drugs was assessed in vitro, Colony-forming assays using human tumor cell lines demonstrated that pretreatment with 30-250 mu M 6AN for 18 h resulted in increased sensitivity to the DNA cross-linking agent cisplatin, with 6-, 11-, and 17-fold decreases in the cisplatin dose that diminishes colony formation by 90% being observed in K562 leukemia cells, A549 non-small cell lung cancer cells, and T98G glioblastoma cells, respectively, Morphological examination revealed increased numbers of apoptotic cells after treatment with 6AN and cisplatin compared to cisplatin alone, 6AN also sensitized cells tomelphalan and nitrogen mustard but not to chlorambucil, 4-hydroperoxycyclophosphamide, etoposide, or daunorubicin, In additional studies undertaken to elucidate the mechanism underlying the sensitization to cisplatin, atomic absorption spectroscopy revealed that 6AN had no effect on the rate of removal of platinum (Pt) adducts from DNA. Instead, 6AN treatment was accompanied by an increase in Pt-DNA adducts that paralleled the degree of sensitization, This effect was not attributable to 6AN-induced decreases in glutathione or NAD(+), because other agents that depleted these detoxification cofactors (buthionine sulfoximineand 3-acetylpyridine, respectively) did not increase Pt-DNA adducts, On the contrary, 6AN treatment increased cellular accumulation of cisplatin, Further experiments revealed that 6AN was metabolized to 6-aminonicotinamide adenine dinucleotide (6ANAD(+)). Concurrent administration of nicotinamide and 6AN had minimal effect on cellular 6AN accumulation but abolished the formation of 6ANAD(+), the increase in Pt-DNA adducts, and the sensitizing effect of 6AN in clonogenic assays. These observations identify 6AN as a potential modulator of cisplatin sensitivity and suggest that the 6AN metabolite 6ANAD(+) exerts this effect by increasing cisplatin accumulation and subsequent formation of Pt-DNA adducts.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 13/07/20 alle ore 18:05:37