Show simple item record

dc.contributor.authorGowan, SMen_US
dc.contributor.authorHarrison, JRen_US
dc.contributor.authorPatterson, Len_US
dc.contributor.authorValenti, Men_US
dc.contributor.authorRead, MAen_US
dc.contributor.authorNeidle, Sen_US
dc.contributor.authorKelland, LRen_US
dc.identifier.citationMOLECULAR PHARMACOLOGY, 2002, 61 pp. 1154 - 1162en_US
dc.description.abstractThe telomerase complex is responsible for telomere maintenance and represents a promising cancer therapeutic target. We describe herein the antitelomerase and antitumor properties of a small-molecule compound designed by computer modeling to interact with and stabilize human G-quadruplex DNA, a structure that may form with telomeric DNA, thereby inhibiting access to telomerase. The 3,6,9-trisubstituted acridine 9-[4-(N,N-dimethylamino) phenylamino]-3,6-bis(3-pyrrolodinopropionamido) acridine (BRACO19) represents one of the most potent cell-free inhibitors of human telomerase yet described (50% inhibitory concentration of 115+/-18 nM). Moreover, in contrast to G-quadruplex interactive agents described previously, BRACO19 did not cause nonspecific acute cytotoxicity at similar concentrations to those required to completely inhibit telomerase activity. There exists a 90-fold differential (mean 50% inhibitory concentration for acute cell kill across seven human tumor cell lines of 10.6+/-0.7 muM). The exposure of 21NT human breast cancer cells, which possess relatively short telomeres, to nonacute cytotoxic concentrations of BRACO19 (2 muM) resulted in a marked reduction in cell growth after only 15 days. This was concomitant with a reduction in intracellular telomerase activity and onset of senescence as indicated by an increase in the number of beta-galactosidase positive-staining cells. Intraperitoneal administration of nontoxic doses of BRACO19 (2 mg/kg) to mice bearing advanced stage A431 human vulval carcinoma subcutaneous xenografts and previously treated with paclitaxel induced a significant increase in antitumor effect compared with that observed with paclitaxel alone. BRACO19 thus represents the first of a “second generation” of G-quadruplex-mediated telomerase/telomere-interactive compounds. It possesses nanomolar potency against telomerase but low nonspecific cytotoxicity, growth inhibitory effects, and induction of senescence in a human breast cancer cell line and, moreover, significant antitumor activity in vivo when administered post paclitaxel to mice bearing a human tumor xenograft carcinoma.en_US
dc.format.extent1154 - 1162en_US
dc.titleA G-quadruplex-interactive potent small-molecule inhibitor of telomerase exhibiting in vitro and in vivo antitumor activityen_US
dc.typeJournal Article
rioxxterms.typeJournal Article/Reviewen_US
pubs.notesaffiliation: Kelland, LR (Reprint Author), Univ London St Georges Hosp, Sch Med, Cranmer Terrace, London SW17 OQS, England. Inst Canc Res, Canc Res Campaign, Ctr Canc Therapeut, Surrey, England. Inst Canc Res, Chester Beatty Labs, CRC, Biomol Struct Unit, London SW3 6JB, England. keywords-plus: HUMAN-CELLS LEADS; HUMAN TUMOR-CELLS; CANCER-CELLS; CATIONIC PORPHYRINS; BREAST-CANCER; DRUG DESIGN; IN-VIVO; DNA; TARGET; DERIVATIVES research-areas: Pharmacology & Pharmacy web-of-science-categories: Pharmacology & Pharmacy number-of-cited-references: 61 times-cited: 217 usage-count-last-180-days: 1 usage-count-since-2013: 26 journal-iso: Mol. Pharmacol. doc-delivery-number: 543ZL unique-id: ISI:000175133700024 oa: gold_or_bronze da: 2018-09-18en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR)
pubs.embargo.termsNot knownen_US
icr.researchteamCancer Pharmacology & Stress Response (CPSR)en_US
dc.contributor.icrauthorGowan, Sharonen_US
dc.contributor.icrauthorKelland, Lloyden_US
dc.contributor.icrauthorNeidle, Stephenen_US

Files in this item


There are no files associated with this item.

This item appears in the following Collection(s)

Show simple item record