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Titolo:
STABLE ANALOGS OF THE ANTITUMOR AGENT TRIMELAMOL RETAIN IN-VITRO CYTOTOXICITY IN DRUG-SENSITIVE AND RESISTANT RODENT AND HUMAN CELL-LINES
Autore:
COLEY HM; JARMAN M; BROOKS N; THORNTON TJ; JUDSON IR;
Indirizzi:
INST CANC RES,DEPT DRUG DEV,15 COTSWOLD RD SUTTON SM2 5NG SURREY ENGLAND HAFSLUND NYCOMBED PHARMA AG A-4021 LINZ AUSTRIA
Titolo Testata:
European journal of cancer
fascicolo: 12, volume: 30A, anno: 1994,
pagine: 1827 - 1836
SICI:
0959-8049(1994)30A:12<1827:SAOTAA>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
INVITRO CYTO-TOXICITY; PHASE-II TRIAL; OVARIAN-CANCER; METABOLIC-ACTIVATION; ACQUIRED-RESISTANCE; CROSS-RESISTANCE; HEXAMETHYLMELAMINE; CARCINOMA; CISPLATIN; PHARMACOKINETICS;
Keywords:
TRIMELAMOL; STABLE ANALOGS; IN VITRO; ALKYLATING-AGENT PLATINUM RESISTANCE; OVARIAN CANCER;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
33
Recensione:
Indirizzi per estratti:
Citazione:
H.M. Coley et al., "STABLE ANALOGS OF THE ANTITUMOR AGENT TRIMELAMOL RETAIN IN-VITRO CYTOTOXICITY IN DRUG-SENSITIVE AND RESISTANT RODENT AND HUMAN CELL-LINES", European journal of cancer, 30A(12), 1994, pp. 1827-1836

Abstract

In spite of clinical activity in heavily-pretreated ovarian cancer, the antitumour s-triazine trimelamol [TM; tris(hydroxymethyl)-tris(methyl)melamine] had to be withdrawn from further clinical studies due to formulation difficulties related to instability. A synthetic programmehas produced tris(hydroxymethyl) analogues containing electron-withdrawing groups in place of methyl-triscyanomethyl CB 7669, tristrifluoroethyl CB 7639, CB 7529 and trispropargyl CB 7547, all showing markedlysuperior stability to TM. Chemosensitivity testing of analogues (MTT assay, continuous exposure) using a panel of rodent and human cell lines showed activity close to that of TM, e.g. for the CH1 human ovariancancer cell line. IC50 values were TM 23.4 mu M, CB 7639 30.5 mu M, CB 7529 29.5 mu M, CB 7547 28.5 mu M and CB 7669 27.3 mu M. CB 7669 andCB 7639 required prolonged exposure (>12 h) in order to exhibit equivalent cytotoxicity to a 2-h exposure to TM. Thus, rather than administration as a single daily dose, the stable analogues may be more suitedto prolonged infusion, which was suggested as being a more beneficialregimen in clinical trials with TM. In line with clinical observations indicating the efficacy of TM in platinum-refractory ovarian cancer,we saw no significant cross-resistance to TM or CB 7529 in a range ofplatinum-sensitive and acquired-resistant cell line pairs or in an alkylating-agent resistant eel line, despite TM's ability to crosslink DNA. Data obtained using cell lines with acquired resistance to TM, CB 7669 and formaldehyde (released in the breakdown of TM) suggest a pivotal role for formaldehyde and a more minor role for alkylating activity in the mechanism of action of the N-(hydroxymethyl)melamines in vitro. Further clinical trials of these compounds are eagerly awaited, andtheir usefulness as second-line chemotherapy for heavily pretreated ovarian cancer deserves further investigation.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 09/04/20 alle ore 13:05:46