Pre-clinical development of the anti-tumour agent CB 7646, bis N-(hydroxymethyl) trimethylmelamine, a stable analogue of trimelamol.
Formulation difficulties prevented the otherwise promising clinical development of the anti-tumour agent trimelamol (TM; tris-[hydroxymethyl]trimethylmelamine]). A synthetic analogue programme resulted in the identification of CB 7646 (bis N-[hydroxymethyl]trimethylmelamine) as a compound with improved stability and favourable formulation characteristics. The in vitro and in vivo activity of CB 7646 was shown to be very similar to that of TM. In addition, curative activities were shown in the PXN/65 human ovarian cancer xenograft and the MX-1 and T-61 human breast cancer xenograft models. The effectiveness of the N-(hydroxymethyl)melamines against platinum-refractory disease was noted in the phase I clinical trial of TM. In line with this finding, the present study confirmed the effective activity of both TM and CB 7646 against various forms of platinum resistance in in vitro models. Curative activity for TM and CB 7646 was seen in the HX110P human ovarian cancer xenograft with acquired carboplatin resistance. Animal studies indicated less neurotoxicity for CB 7646 than for TM. The pharmacokinetic profile of CB 7646 indicated a decreased plasma elimination, indicative of slower in vivo degradation than for TM. CB 7646, therefore, represents a promising candidate for clinical development, designed to supersede TM.
CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, UK.
H M
HM
Coley
M
M
Jarman
N
N
Brooks
T
T
Kubota
P M
PM
Goddard
M
M
Jones
N
N
Lee
M D
MD
Owens
G W
GW
Halbert
I R
IR
Judson
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009422:Nervous System Diseases / Q000139:chemically induced; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010954:Plasmacytoma / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D012996:Solutions; D014183:Transplantation, Heterologous; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014867:Water / Q000737:chemistry
D000970:Antineoplastic Agents; D012996:Solutions; D014227:Triazines; C102255:bis-N-(hydroxymethyl)trimethylmelamine; D014867:Water; C049507:trimelamol; D002945:Cisplatin