Pharmacokinetics and cytotoxicity of B.3839, a molecular combination of 5-fluorouracil and N-(2-chloroethyl)-N-nitrosourea, in a mouse model

Abstract

B.3839 is the prototype compound in a series of novel molecular combinations of chloroethylnitrosoureas and 5-fluorouracil(5-FU) and has been tested against MAC tumours in mice. Previous studies have shown it is moderately active against MAC15A and highly active against MAC13 though this activity is dependent on route of administration. The aim of this study was to determine whether bioavailability could explain this difference in anti-tumour activity. Plasma levels of B.3839 and 5-FU after i.p. and oral administration were measured using HPLC. Non tumour-bearing and MAC26 bearing mice gave almost identical plasma profiles after i.p. administration with the Cmax being 29.8 and 30.4 micrograms ml-1 and t1/2 16 and 15 min. The AUCs were 15.3 and 13.9 micrograms h ml-1 suggesting tumour load had no influence over plasma levels. Oral administration gave a much lower Cmax of 8.0 micrograms ml-1 but an AUC of 15.2 micrograms h ml-1 due to a longer terminal t1/2 (94 min) giving 99% bioavailability. Levels of 5-FU release from B.3839 by either route were considered too small to influence anti-tumour activity. Cytotoxicity assays in vitro against the MAC lines gave IC70 values of 5.3, 13.8 and 8.6 micrograms ml-1 for MAC 26, 13 and 15A respectively after a one hour exposure. Bone marrow toxicity was shown to be less severe than that of TCNU which is currently in clinical trials. The results show bioavailability alone is not enough to explain tumour response. There appears to be a need for a threshold concentration (C) to be maintained for a period of time (t).