A series of cationic porphyrins has been identified as G-quadruplex interac
tive agents (QIAs) that stabilize telomeric G-quadruplex DNA and thereby in
hibit human telomerase; 50% inhibition of telomerase activity was achieved
in HeLa cell-free extract at porphyrin concentrations in the range greater
than or equal to 50 mu M. Cytotoxicity of the porphyrins in vitro was asses
sed in normal human cells (fibroblast and breast) and human tumor cells rep
resenting models selected for high telomerase activity and short telomeres
(breast carcinoma, prostate, and lymphoma). In general, the cytotoxicity (E
C50, effective concentration for 50% inhibition of cell proliferation) agai
nst normal and tumor cells was >50 mu M. The porphyrins were readily absorb
ed into tumor cell nuclei in culture. Inhibition of telomerase activity in
MCF7 cells by subcytotoxic concentrations of TMPyP4 showed time and concent
ration dependence at 1-100 mu M TMPyP4 over 15 days in culture (10 populati
on doubling times). The inhibition of telomerase activity was paralleled by
a cell growth arrest in G(2)-M. These results suggest that relevant biolog
ical effects of porphyrins can be achieved at concentrations that do not ha
ve general cytotoxic effects on cells. Moreover, the data support the conce
pt that a rational, structure-based approach is possible to design novel te
lomere-interactive agents with application to a selective and specific anti
cancer therapy.