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A Novel Cyclic Adenosine Monophosphate Analog Induces Hypercalcemia via Production of 1,25-Dihydroxyvitamin D in Patients with Solid Tumors

Imperial Cancer Research Fund, Medical Oncology Unit, Churchill Hospital (M.P.S., A.J.S., L.L., K.J.O., D.C.T., R.M.W., A.L.H.), Oxford, OX3 7LJ; and Department of Medicine, Manchester Royal Infirmary (E.B.M.), Manchester, M13 9WL, United Kingdom

Address all correspondence and requests for reprints to: Adrian L. Harris, Imperial Cancer Research Fund, Medical Oncology Unit, University of Oxford, Oxford Radcliffe Hospital, Headington, Oxford, United Kingdom OX3 7LJ.

The treatment of cancer patients with conventional chemotherapy is sometimes associated with severe systemic toxicity and only a minimal survival benefit. Because of this, new less toxic and more efficacious treatments have been sought. 8-Chloro-cAMP (8-Cl-cAMP) is one of a new generation of anticancer drugs that act at the level of signal transduction. In preclinical models, 8-Cl-cAMP modulates protein kinase A (PKA) leading to growth inhibition and increased differentiation of cancer cells. 8-Cl-cAMP was given to 16 patients with advanced cancer as an infusion via an indwelling subclavian venous catheter. We showed that 8-Cl-cAMP had a parathyroid hormone-like effect leading to increased synthesis of renal 1,25-dihydroxyvitamin D [up to 14 times the baseline value, median 3.6 times; P = 0.00001 (Student’s paired t test)]. This produced the dose-limiting toxicity of reversible hypercalcemia that could not be controlled by the administration of either pamidronate or dexamethasone. The treatment was otherwise well tolerated, and other cAMP-dependent pathways (cortisol and TSH) were not affected, emphasizing the marked differences between organs in their sensitivity to this cAMP analog. Our results have shown that 8-Cl-cAMP is biologically active, and it is feasible that if the hypercalcemia can be controlled, then this drug may have a role as a single agent, or as a short infusion between cycles of chemotherapy.

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				D. J. Propper, M. P. Saunders, A. J. Salisbury, L. Long, K. J. O'Byrne, J. P. Braybrooke, M. Dowsett, M. Taylor, D. C. Talbot, T. S. Ganesan, et al. Phase I Study of the Novel Cyclic AMP (cAMP) Analogue 8-Chloro-cAMP in Patients with Cancer: Toxicity, Hormonal, and Immunological Effects Clin. Cancer Res., July 1, 1999; 5(7): 1682 - 1689. [Abstract] [Full Text] [PDF]