8-CHLORO-CAMP ENHANCES THE GROWTH-INHIBITORY EFFECT OF CYTOTOXIC DRUGS IN HUMAN COLON-CANCER CELLS

8-Cl-cAMP is a novel agent able to inhibit the growth of a wide variet y of cancer cell types in vitro and in vivo by interfering with the pr otein kinase A type I (PKAI), a protein directly involved in mitogenic signalling and neoplastic transformation. In a recent phase I study c onducted in cancer patients we have demonstrated that 8-Cl-cAMP, at do ses devoid of toxicity, may achieve plasma concentrations in a range p reviously shown effective for cancer cell growth inhibition. In the pr esent study we have investigated the effect of 8-Cl-cAMP in associatio n with cytotoxic drugs acting by different mechanisms of action on the growth of LS174T and GEO human colon cancer cells. We here demonstrat e that 8-Cl-cAMP administered after the cytotoxic drugs does not inter fere with their growth inhibitory effect but rather is additive with m ost of them. Moreover, a synergistic effect was observed when 8-Cl-cAM P was administered after cisplatin or paclitaxel. The sequence of trea tment seems to be important since pretreatment with 8-Cl-cAMP interfer es with the effect of the cytoxic drugs. These results demonstrate tha t 8-Cl-cAMP is not only able to induce cell growth inhibition when use d alone but also exhibit the capacity to enhance the efficacy of diffe rent cytotoxic drugs.