The activity of N-(hydroxymethyl) melamines in fresh human ovarian tumour 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 formulation difficulties due to its inherent instability the development of TM was halted. In vivo studies using a human ovarian cancer xenograft model 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 (60 mg/kg i.p., or 90 mg/kg p.o.) indicated only very modest tumour growth delays. In vitro chemosensitivity testing using primary ovarian tumour 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 xenograft and promising activity was seen in the MX-1 human breast cancer xenograft. In spite of enhanced stability in aqueous solution and good in vitro cytotoxicity, the TM analogues CB 7669 (triscyanomethyl) and CB 7639 (tristrifluoroethyl) showed disappointing in vivo antitumour activity which may be explained by the need for prolonged exposure. TM analogues with intermediate stability are currently under development in an effort to further the clinical development of this promising group of antitumour agents.
Coley
H M
HM
CRC Centre for Cancer Therapeutics, Sutton, Surrey, U.K.
Jarman
M
M
Jones
M
M
Sargent
J M
JM
Kubota
T
T
Lee
N C
NC
Goddard
P M
PM
Elgie
A W
AW
Williamson
C
C
Taylor
C G
CG
Judson
I R
IR
D006585:Altretamine; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014227:Triazines / Q000138:chemical synthesis / Q000627:therapeutic use* / Q000633:toxicity*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D014227:Triazines; C049507:trimelamol; D006585:Altretamine