The history of the development and clinical use of CB 3717 and ICI D1694.
The antifolate thymidylate synthase inhibitors represent an exciting area in new drug development and show that with an understanding of the structural basis for toxicity, new drugs can be synthesised which have a more manageable spectrum of side effects whilst retaining activity. ICI D1694 does not show the nephrotoxicity which affected the development of CB 3717. Myelosuppression and gut toxicity are seen and are more typical of the toxicities one associates with this class of agent. Changes in hepatic enzymes have been seen with both drugs, and are also seen with other anti-folates including MTX, but these changes settle with repeat dosing and with cessation of treatment. We await the results of the planned phase II trials of ICI D1694 with great interest.
Clarke
S J
SJ
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, UK.
Jackman
A L
AL
Judson
I R
IR
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000266:history*; D017321:Clinical Trials, Phase I as Topic; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000266:history; D049673:History, 20th Century; D015394:Molecular Structure; D011799:Quinazolines / Q000266:history*; D013876:Thiophenes / Q000266:history*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D006113:United Kingdom
D000964:Antimetabolites, Antineoplastic; D011799:Quinazolines; D013876:Thiophenes; C031662:CB 3717; D005492:Folic Acid; D013940:Thymidylate Synthase; C068874:raltitrexed