| Abstract: |
8-Chloro-cyclic AMP (8-Cl-cAMP), a site-selective cAMP analogue, is a specific inhibitor of type I cAMP-dependent protein kinase (PKAI) and induces growth Inhibition in several human and rodent tumor cell lines. The anti-epidermal growth factor receptor (EGFR) mAb 528 is a blocking antibody able to inhibit the in vitro and in vivo growth of several human cancer cell lines that express functional EGFRs. Since enhanced levels of PKAI are generally found in tumor cells and an increase in PKAI expression is induced by transformation through a transforming growth factor α/EGFR autocrine pathway, we have evaluated whether treatment with mAb 528 in combination with 8-C1- cAMP may have an additive or synergistic growth inhibitory effect on human cancer cells. A dose-dependent inhibition of monolayer cell growth was observed in two human colon cancer cell lines (GEO and CBS) and in a human breast cancer cell line (MDA-468) by treatment with either mAb 528 or 8-Cl-cAMP with 50% inhibitory concentration of 2-10 μg/ml or 20-25 μM, respectively. The combined treatment with low noninhibitory doses of mAb 528 (0.25 μg/ml) and with 8-Cl-cAMP had a more than additive growth inhibitory effect with a 3- to 5-fold reduction in the 8-C1- cAMP 50% inhibitory concentration in all cell lines tested. This combined treatment was similarly effective in inhibiting the soft agar cloning efficiency of GEO cells. 8-Cl-cAMP treatment of GEO cells induced a dose-dependent increase in cell membrane-associated EGFRs with a maximum 3- to fold increase within 48-72 h of treatment. These results suggest that a double blockade of the PKAI serine-threonine kinase-dependent and of the EGFR tyrosine kinase-dependent pathways is potentially useful in cancer therapy. © 1995, American Association for Cancer Research. All rights reserved. |
| Keywords: |
epidermal growth factor; controlled study; human cell; drug potentiation; antineoplastic agents; cell cycle; cell division; epidermal growth factor receptor; receptor, epidermal growth factor; cancer cell culture; tumor cells, cultured; breast neoplasms; monoclonal antibody; antibodies, monoclonal; kinetics; cancer cell; dna fragmentation; human; female; priority journal; article; support, non-u.s. gov't; 8 chloroadenosine 3',5' phosphate; 8-bromo cyclic adenosine monophosphate
|
