The site-selective cyclic AMP analogue 8-chloro-cAMP (8-Cl-cAMP) is able to inhibit the growth of a wide variety of cancer cell lines in vitro and in vivo. 8-Cl-cAMP has been extensively investigated as a new potential anticancer agent and, more recently, preclinical Phase I studies have been conducted in animal models to study its toxicity. We have conducted the first Phase I trial with 8-Cl-cAMP to define the maximum tolerated dose, toxicity, plasma drug levels, and immunological effects in patients with cancers refractory to standard treatments. We have 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-week 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 cytolytic 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 were the dose-limiting toxicity. The maximum tolerated dose (0.2 mg/kg/h) determined a grade 1 increase in serum creatinine. An increase in calcium levels was observed in several patients. The 8-Cl-cAMP plasma concentrations obtained at the steady state were in the range previously shown to be effective for cancer cell growth inhibition in vitro. Interleukin 2 receptor alpha expression, natural killer cell number, and cytolytic activity from peripheral blood lymphocytes were markedly increased after 8-Cl-cAMP administration at all dose levels. In conclusion, at doses below the maximum tolerated dose, 8-Cl-cAMP was not toxic but reached plasma concentrations in the potential therapeutic range for growth inhibition. Moreover, 8-Cl-cAMP determined a marked biomodulatory effect and showed antitumor activity.

Phase I clinical study with 8-Chloro-cAMP and evaluation of immunological effects in cancer patients.

PEPE, Stefano;
1995

Abstract

The site-selective cyclic AMP analogue 8-chloro-cAMP (8-Cl-cAMP) is able to inhibit the growth of a wide variety of cancer cell lines in vitro and in vivo. 8-Cl-cAMP has been extensively investigated as a new potential anticancer agent and, more recently, preclinical Phase I studies have been conducted in animal models to study its toxicity. We have conducted the first Phase I trial with 8-Cl-cAMP to define the maximum tolerated dose, toxicity, plasma drug levels, and immunological effects in patients with cancers refractory to standard treatments. We have 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-week 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 cytolytic 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 were the dose-limiting toxicity. The maximum tolerated dose (0.2 mg/kg/h) determined a grade 1 increase in serum creatinine. An increase in calcium levels was observed in several patients. The 8-Cl-cAMP plasma concentrations obtained at the steady state were in the range previously shown to be effective for cancer cell growth inhibition in vitro. Interleukin 2 receptor alpha expression, natural killer cell number, and cytolytic activity from peripheral blood lymphocytes were markedly increased after 8-Cl-cAMP administration at all dose levels. In conclusion, at doses below the maximum tolerated dose, 8-Cl-cAMP was not toxic but reached plasma concentrations in the potential therapeutic range for growth inhibition. Moreover, 8-Cl-cAMP determined a marked biomodulatory effect and showed antitumor activity.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11386/3104507
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