THE ACTIVITY OF N-(HYDROXYMETHYL) MELAMINES IN FRESH HUMAN OVARIAN TUMOR-CELLS AND XENOGRAFTS

Trimelamol (TM) was developed as a water soluble analogue of the oral chemotherapeutic agent hexamethyl-melamine (HMM), to be administered i .v., in an effort to avoid dose limiting emesis. Because of formulatio n difficulties due to its inherent instability the development of TM w as halted. In vivo studies using a human ovarian cancer xenograft mode l PXN/65 showed TM to be curative in the dose range of 15-60 mg/kg i.p . daily x 5, for 4 weeks. Conversely, HMM given at the highest dose (6 0 mg/kg i.p., or 90 mg/kg p.o.) indicated only very modest tumour grow th delays. In vitro chemosensitivity testing using primary ovarian tum our cultures showed that in 12/23 cases indicating reduced sensitivity to cisplatin or carboplatin, sensitivity to TM was increased. TM was curative in the carboplatin-resistant HX 110P human ovarian cancer xen ograft and promising activity was seen in the MX-1 human breast cancer xenograft. In spite of enhanced stability in aqueous solution and goo d in vitro cytotoxicity, the TM analogues CB 7669 (triscyanomethyl) an d CB 7639 (tristrifluoroethyl) showed disappointing in vivo antitumour activity which may be explained by the need fro prolonged exposure. T m analogues with intermediate stability are currently under developmen t in an effort to further the clinical development of this promising g roup of antitumour agents.