PHASE-I CLINICAL-STUDY WITH 8-CHLORO-CAMP AND EVALUATION OF IMMUNOLOGICAL EFFECTS IN CANCER-PATIENTS

The site-selective cyclic AMP analogue 8-chloro-cAMP (8-Cl-cAMP) is ab le to inhibit the growth of a wide variety of cancer cell lines in vit ro and in vivo. 8-Cl-cAMP has been extensively investigated as a new p otential anticancer agent and, more recently, preclinical Phase I stud ies have been conducted in animal models to study its toxicity. We hav e conducted the first Phase I trial with 8-Cl-cAMP to define the maxim um tolerated dose, toxicity, plasma drug levels, and immunological eff ects in patients with cancers refractory to standard treatments. We ha ve administered 36 courses of 8-Cl-cAMP to 17 patients by continous i. v. infusion of the drug for 5 days/week for 2 weeks followed by a 1-we ek rest period. Six increasing dose levels, from 0.01 to 0.25 mg/kg/h, were explored. Drug plasma levels were determined and the expression of interleukin 2 receptor alpha, amount of natural killer cells, and c ytolytic activity against K562 cells were measured in peripheral blood lymphocytes. A grade 4 and a grade 3 increase in serum creatinine and a grade 2 increase in blood urea nitrogen observed in two patients we re the dose-limiting toxicity. The maximum tolerated dose (0.2 mg/kg/k ) determined a grade 1 increase in serum creatinine. An increase in ca lcium levels was observed in several patients. The 8-Cl-cAMP plasma co ncentrations obtained at the steady state were in the range previously shown to be effective for cancer cell growth inhibition in vitro. Int erleukin 2 receptor alpha expression, natural killer cell number, and cytolytic activity from peripheral blood lymphocytes were markedly inc reased after 8-Cl-cAMP administration at all dose levels. In conclusio n, at doses below the maximum tolerated dose, 8-Cl-cAMP was not toxic but reached plasma concentrations in the potential therapeutic range f or growth inhibition. Moreover, 8-Cl-cAMP determined a marked biomodul atory effect and showed antitumor activity.