N-(Hydroxymethyl) melamines.
1. The N-(hydroxymethyl) melamines are analogs of the antitumor agent hexamethylmelamine (HMM) which do not require bioactivation to exert their antitumor effects. 2. Trimelamol (N2,N4,N6-trihydroxymethyl-N2,N4,N6-trimethylmelamine; TM) was developed as a water-soluble antitumor agent for intravenous administration. 3. Phase I and II trials of TM showed promising activity versus platinum-refractory ovarian cancer, but unfortunately further clinical development was halted due to formulation difficulties. 4. Stable analogs of TM were synthesized in an effort to overcome this shortcoming and these were evaluated in a number of in vitro and in vivo studies. 5. While the stable analogs showed good in vitro cytotoxicity in tumor cell lines, only one analog, CB7646 [bis-N-(hydroxymethyl)trimethylmelamine], showed comparable in vivo antitumor activity to that seen for TM. 6. Both TM and CB7646 were curative in human ovarian and breast cancer xenograft models, including the HX110P ovarian cancer xenograft with acquired resistance to carboplatin. 7. As CB7646 possesses favorable formulation characteristics, relating to its superior stability over that for TM, it is currently being developed for phase I clinical trial. 8. The N-(hydroxymethyl) melamines are capable of overcoming many forms of drug resistance, based on data obtained in in vitro and in vivo studies, and thus show promise as agents in the treatment of heavily pretreated, refractive tumors.
Coley
H M
HM
CRC Center for Cancer Therapeutics, Institute of Cancer Research, Belmont, Sutton, Surrey, UK.
D006585:Altretamine / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D014227:Triazines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D014227:Triazines; C102255:bis-N-(hydroxymethyl)trimethylmelamine; C049507:trimelamol; D006585:Altretamine