Pharmacokinetics and anti-tumour activity of B.4152, a reactive molecular combination of 5-fluorouracil and N-(2-chloroethyl)-N-nitrosourea, and its uracil analogue.

The original design of the previously described molecular combinations of 5-fluorouracil (5-FU) and a chloroethyl nitrosourea (CNU) moiety was on the basis that a single drug would be able to deliver two cytotoxic moieties to tumours following hydrolytic release in vivo of free 5-FU. Subsequently experiments have shown to date that the observed activity is due mainly to the alkylating effect of the CNU. This study investigates a molecular combination of 5-FU/CNU (B.4152) which is the most readily hydrolysed under acid conditions of all the 5-FU seco-nucleosides so far prepared, and compares it with the unsubstituted uracil analogue B.4184. In vitro cytotoxicity studies against three murine colon tumour cell lines showed large differences in IC50 values between the two analogues, those for B.4184 being > 10-fold greater than those for B.4152. These differences could not be accounted for by drug stability as half-lives in tissue culture medium were similar. In vivo, B.4152 was also more active against the tumour lines and was marrow sparing at therapeutic doses. Pharmacokinetic studies demonstrated that improved 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 important role to play.