title: A novel cyclic adenosine monophosphate analog induces hypercalcemia via production of 1,25-dihydroxyvitamin D in patients with solid tumors.
abstract: 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.
authors.affiliation: Imperial Cancer Research Fund, Medical Oncology Unit, Churchill Hospital, Oxford, United Kingdom.
authors.forename: M P
authors.initials: MP
authors.lastname: Saunders
authors.forename: A J
authors.initials: AJ
authors.lastname: Salisbury
authors.forename: K J
authors.initials: KJ
authors.lastname: O'Byrne
authors.forename: L
authors.initials: L
authors.lastname: Long
authors.forename: R M
authors.initials: RM
authors.lastname: Whitehouse
authors.forename: D C
authors.initials: DC
authors.lastname: Talbot
authors.forename: E B
authors.initials: EB
authors.lastname: Mawer
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D000242:Cyclic AMP / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D006801:Humans; D006934:Hypercalcemia / Q000139:chemically induced*; D009369:Neoplasms / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000097:blood; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D010281:Parathyroid Hormone; D014807:Vitamin D; D015124:8-Bromo Cyclic Adenosine Monophosphate; C097949:1,25-dihydroxyvitamin D; C044258:8-chloro-cyclic adenosine monophosphate; D000242:Cyclic AMP