PHARMACOKINETICS AND ANTITUMOR-ACTIVITY OF B.4152, A REACTIVE MOLECULAR COMBINATION OF 5-FLUOROURACIL AND N-(2-CHLOROETHYL)-N-NITROSOUREA, AND ITS URACIL ANALOG

The original design of the previously described molecular combinations of 5-fluorouracil (5-FU) and a chloroethyl nitrosourea (CNU) moiety w as on the basis that a single drug would be able to deliver two cytoto xic moieties to tumours following hydrolytic release in vivo of free 5 -FU. Subsequently, experiments have shown to date that the observed ac tivity is due mainly to the alkylating effect of the CNU. This study i nvestigates a molecular combination of 5-FU/CNU (B.4152) which is the most readily hydrolysed under acid conditions of all the 5-FU seco-nuc leosides so far prepared, and compares it with the unsubstituted uraci l analogue B.4184. In vitro cytotoxicity studies against three murine colon tumour cell lines showed large differences in IC50 values betwee n the two analogues, those for B.4184 being >10-fold greater than thos e for B.4152. These differences could not be accounted for by drug sta bility as half-lives in tissue culture medium were similar. In vivo, B .4152 was also more active against the tumour lines and was marrow spa ring at therapeutic doses. Pharmacokinetic studies demonstrated that i mproved activity was not due to release of free 5-FU, but differences in activity, toxicity and plasma pharmacokinetics between B.4152 and B .4184 are quite marked, indicating that the 5-FU moiety does have an i mportant role to play.