Site-selective cyclic AMP analogs provide a new approach in the control of cancer cell growth.
Site-selective cyclic AMP analogs bind to site 1 or site 2 of the known cAMP-binding sites depending on the position of substituents on the purine ring, either at C-2 and C-8 (site 1) or at C-6 (site 2). The growth inhibitory effect of such site-selective cAMP analogs used in this investigation with 15 human cancer cell lines surpassed that of analogs previously tested. The most potent analogs were 8-chloro, N6-benzyl and N6-phenyl-8-p-chlorophenylthio-cAMP. The combination of a C-8 with an N6 analog had synergistic effects. The 24 site-selective analogs tested produced growth inhibition ranging from 30 to 80% at micromolar concentrations with no sign of toxic effects. Growth inhibition was not due to a block in a specific phase of the cell cycle but paralleled a change in cell morphology, an increase of the RII cAMP receptor protein and a decrease of p21 ras protein. Since the adenosine counterpart of the 8-chloro analog produced G1 synchronization without affecting the RII and p21 ras protein levels, it is unlikely that an adenosine metabolite is involved in the analog effect. Site-selective cAMP analogs thus provide a new biological tool for control of cancer growth.
Katsaros
D
D
Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, MD 20892.
Tortora
G
G
Tagliaferri
P
P
Clair
T
T
Ally
S
S
Neckers
L
L
Robins
R K
RK
Cho-Chung
Y S
YS
D001943:Breast Neoplasms; D003994:Bucladesine / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000473:pathology
D003994:Bucladesine; D000242:Cyclic AMP