PHARMACOKINETICS, METABOLISM AND TUMOR DISPOSITION OF 8-CHLOROADENOSINE 3',5'-MONOPHOSPHATE IN BREAST-CANCER PATIENTS AND XENOGRAFT BEARINGMICE

Background: 8-Chloroadenosine 3',5'-monophosphate (8-Cl-cAMP) is under going phase I clinical trials as an anticancer drug. However, there is debate as to whether it is a prodrug for its 8-Cl-adenosine metabolit e. Design: Pharmacokinetics, metabolism and tumour disposition studies have been performed in 7 breast cancer patients receiving continuous infusion (28 day) 8-Cl-cAMP (0.54 or 1.08 mg/kg/day) and tumour biopsi es were obtained before and on the last day of infusion. Parallel stud ies were performed in nude mice bearing the HT29 human colon cancer xe nograft after continuous infusion (7 day) of active drug doses (50 or 100 mg/kg/day). Results: Steady state plasma levels (C-ss) of 8-Cl-cAM P in patients ranged from 0.15-0.72 mu M but 8-Cl-adenosine was not de tected in plasma. In contrast, 8-Cl-cAMP was not detectable in 3 tumou r biopsies but 8-Cl-adenosine was present in 2 samples at high concent rations (1.33 and 2.02 mu M). In mice, C-ss of 8-Cl-cAMP ranged from 3 .2-4.6 mu M and 8-Cl adenosine was present in plasma only at the highe r dose (100 mg/kg/day, peak concentration of 2.3 mu M). In the HT29 xe nograft, 8-Cl-cAMP levels were considerably lower than in plasma (0.37 -1.22 mu M) while 8-Cl-adenosine was present at 5.3-21.0 mu M and 8-Cl -AMP was found at 11.3-35.7 mu M. Conclusions: The fate of 8-Cl-cAMP i n human tumours is characterised by extensive metabolism to products w hich are not generally observed in plasma. These data raise the possib ility that 8-Cl-cAMP is a prodrug for a product of its metabolism in h uman tumours.