Phase I Study of the Novel Cyclic AMP (cAMP) Analogue 8-Chloro-cAMP in Patients with Cancer: Toxicity, Hormonal, and Immunological Effects

• Published in: Clinical cancer research 1999-07, Vol.5 (7), p.1682-1689
• Main Authors: PROPPER, D. J, SAUNDERS, M. P, HARRIS, A. L, SALISBURY, A. J, LONG, L, O'BYRNE, K. J, BRAYBROOKE, J. P, DOWSETT, M, TAYLOR, M, TALBOT, D. C, GANESAN, T. S
• Format: Article
• Language: English
• Subjects: 8-Bromo Cyclic Adenosine Monophosphate - adverse effects; 8-Bromo Cyclic Adenosine Monophosphate - analogs & derivatives; 8-Bromo Cyclic Adenosine Monophosphate - pharmacokinetics; 8-Bromo Cyclic Adenosine Monophosphate - therapeutic use; Adult; Aged; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Chemotherapy; Cytokines - metabolism; Female; Hormones - metabolism; Humans; Hypercalcemia - chemically induced; Kidney - drug effects; Liver - drug effects; Lymphocyte Subsets - drug effects; Lymphocyte Subsets - metabolism; Male; Medical sciences; Middle Aged; Nausea - chemically induced; Neoplasms - drug therapy; Neoplasms - metabolism; Pharmacology. Drug treatments; Treatment Outcome; Vomiting - chemically induced
• ISSN: 1078-0432; 1557-3265

The cyclic AMP (cAMP)-dependent protein kinase regulatory subunit RI is overexpressed in cancer cells. 8-Chloro-cAMP (8-Cl-cAMP) is an RII site-specific analogue that down-regulates RI and inhibits the growth of a wide range of cancer cells in vitro and in vivo . We performed a Phase I trial of 8-Cl-cAMP in 32 patients with malignancies that were refractory to standard treatments. 8-Cl-cAMP was initially given in a 1-month cycle by constant infusion at 0.005 mg/kg/h for 21 days, followed by 1 week of rest. The dose was escalated to 0.045 mg/kg/h, but hypercalcemia became the dose-limiting toxicity. The length of drug administration was, therefore, reduced to 5 days per week for the first 3 weeks of the cycle, but it was not possible to increase the drug dose without producing hypercalcemia. Hence, the length of drug administration was reduced to 3 days per week for the first 3 weeks of the cycle. The maximum tolerated dose for this regimen was 0.15 mg/kg/h, and the dose-limiting toxicities were reversible hypercalcemia and hepatotoxicity. Stable disease for ≥4 months was observed in two patients treated at ≥0.045 mg/kg. cAMP-dependent protein kinase is involved in hormone- and cytokine-mediated signaling, and so representative hormone, cytokine, and peripheral lymphocyte subsets were measured. The drug had a parathyroid hormone-like effect on calcium homeostasis and significantly increased circulating luteinizing hormone and 17-hydoxyprogesterone levels ( P < 0.02 and P < 0.0006, respectively). We conclude that 8-Cl-cAMP is well tolerated without attendant myelotoxicity, and in this study, it was associated with biological effects. In Phase II studies, a dose of 0.11 mg/kg/h for 3 days per week would be appropriate.