Phase I study of the novel cyclic AMP (cAMP) analogue 8-chloro-cAMP in patients with cancer: toxicity, hormonal, and immunological effects.

Abstract

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 > or =4 months was observed in two patients treated at > or =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.

• Authors: 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, A L Harris
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 5 Issue 7 Pg. 1682-9 (Jul 1999) ISSN: 1078-0432 [Print] United States
• PMID: 10430069 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• Cytokines
• Hormones
• 8-Bromo Cyclic Adenosine Monophosphate
• 8-chloro-cyclic adenosine monophosphate

Topics

• 8-Bromo Cyclic Adenosine Monophosphate (adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Adult
• Aged
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Cytokines (metabolism)
• Female
• Hormones (metabolism)
• Humans
• Hypercalcemia (chemically induced)
• Kidney (drug effects)
• Liver (drug effects)
• Lymphocyte Subsets (drug effects, metabolism)
• Male
• Middle Aged
• Nausea (chemically induced)
• Neoplasms (drug therapy, metabolism)
• Treatment Outcome
• Vomiting (chemically induced)