Pharmacokinetics, metabolism and tumour disposition of 8-chloroadenosine 3',5'-monophosphate in breast cancer patients and xenograft bearing mice
| Autor: | D. J. Burns, Jean A. Mackay, A.A. Ritchie, R. C. F. Leonard, William R. Miller, Jeffrey Cummings, Simon P. Langdon, P.K. Stockman |
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| Rok vydání: | 1996 |
| Předmět: |
medicine.medical_specialty
Metabolite medicine.medical_treatment Transplantation Heterologous Cmax 8-Bromo Cyclic Adenosine Monophosphate Mice Nude Antineoplastic Agents Breast Neoplasms Mice chemistry.chemical_compound Pharmacokinetics Internal medicine medicine Animals Humans Distribution (pharmacology) Prodrugs Tissue Distribution Infusions Intravenous Chemotherapy business.industry Parallel study Hematology Prodrug Adenosine Endocrinology Oncology chemistry Colonic Neoplasms business medicine.drug |
| Zdroj: | Annals of Oncology. 7:291-296 |
| ISSN: | 0923-7534 |
| Popis: | BACKGROUND 8-Chloroadenosine 3',5'-monophosphate (8-Cl-cAMP) is undergoing phase I clinical trials as an anticancer drug. However, there is debate as to whether it is a prodrug for its 8-Cl-adenosine metabolite. 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 biopsies were obtained before and on the last day of infusion. Parallel studies were performed in nude mice bearing the HT29 human colon cancer xenograft after continuous infusion (7 day) of active drug doses (50 or 100 mg/kg/day). RESULTS Steady state plasma levels (Css) of 8-Cl-cAMP in patients ranged from 0.15-0.72 microM but 8-Cl-adenosine was not detected in plasma. In contrast, 8-Cl-cAMP was not detectable in 3 tumour biopsies but 8-Cl-adenosine was present in 2 samples at high concentrations (1.33 and 2.02 microM). In mice, Css of 8-Cl-cAMP ranged from 3.2-4.6 microM and 8-Cl adenosine was present in plasma only at the higher dose (100 mg/kg/day, peak concentration of 2.3 microM). In the HT29 xenograft, 8-Cl-cAMP levels were considerably lower than in plasma (0.37-1.22 microM) while 8-Cl-adenosine was present at 5.3-21.0 microM and 8-Cl-AMP was found at 11.3-35.7 microM. CONCLUSIONS The fate of 8-Cl-cAMP in human tumours is characterised by extensive metabolism to products which are not generally observed in plasma. These data raise the possibility that 8-Cl-cAMP is a prodrug for a product of its metabolism in human tumours. |
| Databáze: | OpenAIRE |
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