Dj. Propper 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 CANC R, 5(7), 1999, pp. 1682-1689
The cyclic AMP (cAMP)-dependent protein kinase regulatory subunit RI is ove
rexpressed in cancer cells. 8-Chloro-cAMP (8-Cl-cAMP) is an RII site-specif
ic 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 trea
tments. 8-Cl-cAMP was initially given in a 1-month cycle by constant infusi
on at 0.005 mg/kg/h for 21 days, followed by 1 week of rest. The dose was e
scalated to 0.045 mg/kg/h, but hypercalcemia became the dose-limiting toxic
ity. The length of drug administration was, therefore, reduced to 5 days pe
r week for the first 3 weeks of the cycle, but it was not possible to incre
ase the drug dose without producing hypercalcemia. Hence, the length of dru
g administration was reduced to 3 days per week for the first 3 weeks of th
e cycle. The maximum tolerated dose for this regimen was 0.15 mg/kg/h, and
the dose-limiting toxicities were reversible hypercalcemia and hepatotoxici
ty. Stable disease for greater than or equal to 4 months was observed in tw
o patients treated at greater than or equal to 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 wer
e measured. The drug had a parathyroid hormone-like effect on calcium homeo
stasis and significantly increased circulating luteinizing hormone and 17-h
ydoxyprogesterone levels (P < 0.02 and P < 0.0006, respectively). We conclu
de 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.