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melamine] had to be withdrawn from further clinical studies due to formulation difficulties related to instability.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 programme has 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 markedly superior 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
ovarian cancer cell line. IC50 values were TM 23.4 microM, CB 7639 30.5 microM, CB 7529 29.5 microM, CB 7547 28.5 microM and CB 7669 27.3 microM. CB 7669 and CB 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 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
alkylating-agent resistant cell 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, and their usefulness as second-line
chemotherapy for heavily pretreated
ovarian cancer deserves further investigation.