STABLE ANALOGS OF THE ANTITUMOR AGENT TRIMELAMOL RETAIN IN-VITRO CYTOTOXICITY IN DRUG-SENSITIVE AND RESISTANT RODENT AND HUMAN CELL-LINES

In spite of clinical activity in heavily-pretreated ovarian cancer, th e antitumour s-triazine trimelamol [TM; tris(hydroxymethyl)-tris(methy l)melamine] had to be withdrawn from further clinical studies due to f ormulation difficulties related to instability. A synthetic programme has produced tris(hydroxymethyl) analogues containing electron-withdra wing groups in place of methyl-triscyanomethyl CB 7669, tristrifluoroe thyl CB 7639, CB 7529 and trispropargyl CB 7547, all showing markedly superior stability to TM. Chemosensitivity testing of analogues (MTT a ssay, continuous exposure) using a panel of rodent and human cell line s showed activity close to that of TM, e.g. for the CH1 human ovarian cancer 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 and CB 7639 required prolonged exposure (>12 h) in order to exhibit equiva lent cytotoxicity to a 2-h exposure to TM. Thus, rather than administr ation as a single daily dose, the stable analogues may be more suited to prolonged infusion, which was suggested as being a more beneficial regimen 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 of platinum-sensitive and acquired-resistant cell line pairs or in an alk ylating-agent resistant eel line, despite TM's ability to crosslink DN A. Data obtained using cell lines with acquired resistance to TM, CB 7 669 and formaldehyde (released in the breakdown of TM) suggest a pivot al 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, and their usefulness as second-line chemotherapy for heavily pretreated ov arian cancer deserves further investigation.