![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 61, Issue 5, 1154-1162, May 2002
Cancer Research Campaign (CRC) Center for Cancer Therapeutics,
Institute of Cancer Research, Surrey, United Kingdom (S.M.G., L.P.,
M.V., L.R.K.); and CRC Biomolecular Structure Unit, Chester Beatty
Laboratories, Institute of Cancer Research, London, United Kingdom
(J.R.H., M.A.R., S.N.)
The 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 µM). The exposure of 21NT human breast cancer cells, which possess relatively short telomeres, to nonacute cytotoxic concentrations of BRACO19 (2 µM) 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 
-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.
This article has been cited by other articles:
|
|
 |
|
  A. De Cian, G. Cristofari, P. Reichenbach, E. De Lemos, D. Monchaud, M.-P. Teulade-Fichou, K. Shin-ya, L. Lacroix, J. Lingner, and J.-L. Mergny Reevaluation of telomerase inhibition by quadruplex ligands and their mechanisms of action PNAS, October 30, 2007; 104(44): 17347 - 17352. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Kelland Targeting the Limitless Replicative Potential of Cancer: The Telomerase/Telomere Pathway Clin. Cancer Res., September 1, 2007; 13(17): 4960 - 4963. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Barbieri, A. R. Srinivasan, S. G. Rzuczek, J. E. Rice, E. J. LaVoie, and D. S. Pilch Defining the mode, energetics and specificity with which a macrocyclic hexaoxazole binds to human telomeric G-quadruplex DNA Nucleic Acids Res., May 11, 2007; 35(10): 3272 - 3286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Cian and J.-L. Mergny Quadruplex ligands may act as molecular chaperones for tetramolecular quadruplex formation Nucleic Acids Res., April 3, 2007; 35(8): 2483 - 2493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Gomez, T. Wenner, B. Brassart, C. Douarre, M.-F. O'Donohue, V. El Khoury, K. Shin-ya, H. Morjani, C. Trentesaux, and J.-F. Riou Telomestatin-induced Telomere Uncapping Is Modulated by POT1 through G-overhang Extension in HT1080 Human Tumor Cells J. Biol. Chem., December 15, 2006; 281(50): 38721 - 38729. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Gill, S. A. Strobel, and J. P. Loria Crystallization and characterization of the thallium form of the Oxytricha nova G-quadruplex Nucleic Acids Res., September 11, 2006; 34(16): 4506 - 4514. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Cookson, F. Dai, V. Smith, R. A. Heald, C. A. Laughton, M. F. G. Stevens, and A. M. Burger Pharmacodynamics of the G-Quadruplex-Stabilizing Telomerase Inhibitor 3,11-Difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) in Vitro: Activity in Human Tumor Cells Correlates with Telomere Length and Can Be Enhanced, or Antagonized, with Cytotoxic Agents Mol. Pharmacol., December 1, 2005; 68(6): 1551 - 1558. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Vaughn, S. D. Creacy, E. D. Routh, C. Joyner-Butt, G. S. Jenkins, S. Pauli, Y. Nagamine, and S. A. Akman The DEXH Protein Product of the DHX36 Gene Is the Major Source of Tetramolecular Quadruplex G4-DNA Resolving Activity in HeLa Cell Lysates J. Biol. Chem., November 18, 2005; 280(46): 38117 - 38120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Granotier, G. Pennarun, L. Riou, F. Hoffschir, L. R. Gauthier, A. De Cian, D. Gomez, E. Mandine, J.-F. Riou, J.-L. Mergny, et al. Preferential binding of a G-quadruplex ligand to human chromosome ends Nucleic Acids Res., July 28, 2005; 33(13): 4182 - 4190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Douarre, D. Gomez, H. Morjani, J.-M. Zahm, M.-F. O'Donohue, L. Eddabra, P. Mailliet, J.-F. Riou, and C. Trentesaux Overexpression of Bcl-2 is associated with apoptotic resistance to the G-quadruplex ligand 12459 but is not sufficient to confer resistance to long-term senescence Nucleic Acids Res., April 14, 2005; 33(7): 2192 - 2203. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. N. Rujan, J. C. Meleney, and P. H. Bolton Vertebrate telomere repeat DNAs favor external loop propeller quadruplex structures in the presence of high concentrations of potassium Nucleic Acids Res., April 7, 2005; 33(6): 2022 - 2031. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Burger, F. Dai, C. M. Schultes, A. P. Reszka, M. J. Moore, J. A. Double, and S. Neidle The G-Quadruplex-Interactive Molecule BRACO-19 Inhibits Tumor Growth, Consistent with Telomere Targeting and Interference with Telomerase Function Cancer Res., February 15, 2005; 65(4): 1489 - 1496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Leonetti, S. Amodei, C. D'Angelo, A. Rizzo, B. Benassi, A. Antonelli, R. Elli, M. F. G. Stevens, M. D'Incalci, G. Zupi, et al. Biological Activity of the G-Quadruplex Ligand RHPS4 (3,11-Difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate) Is Associated with Telomere Capping Alteration Mol. Pharmacol., November 1, 2004; 66(5): 1138 - 1146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Gomez, R. Paterski, T. Lemarteleur, K. Shin-ya, J.-L. Mergny, and J.-F. Riou Interaction of Telomestatin with the Telomeric Single-strand Overhang J. Biol. Chem., October 1, 2004; 279(40): 41487 - 41494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Incles, C. M. Schultes, H. Kempski, H. Koehler, L. R. Kelland, and S. Neidle A G-quadruplex telomere targeting agent produces p16-associated senescence and chromosomal fusions in human prostate cancer cells Mol. Cancer Ther., October 1, 2004; 3(10): 1201 - 1206. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Biroccio and C. Leonetti Telomerase as a new target for the treatment of hormone-refractory prostate cancer Endocr. Relat. Cancer, September 1, 2004; 11(3): 407 - 421. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Fadrna, N. Spackova, R. Stefl, J. Koca, T. E. Cheatham 3rd, and J. Sponer Molecular Dynamics Simulations of Guanine Quadruplex Loops: Advances and Force Field Limitations Biophys. J., July 1, 2004; 87(1): 227 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Gomez, T. Lemarteleur, L. Lacroix, P. Mailliet, J.-L. Mergny, and J.-F. Riou Telomerase downregulation induced by the G-quadruplex ligand 12459 in A549 cells is mediated by hTERT RNA alternative splicing Nucleic Acids Res., January 16, 2004; 32(1): 371 - 379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Gomez, N. Aouali, A. Londono-Vallejo, L. Lacroix, F. Megnin-Chanet, T. Lemarteleur, C. Douarre, K. Shin-ya, P. Mailliet, C. Trentesaux, et al. Resistance to the Short Term Antiproliferative Activity of the G-quadruplex Ligand 12459 Is Associated with Telomerase Overexpression and Telomere Capping Alteration J. Biol. Chem., December 12, 2003; 278(50): 50554 - 50562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Incles, C. M. Schultes, L. R. Kelland, and S. Neidle Acquired Cellular Resistance to Flavopiridol in a Human Colon Carcinoma Cell Line Involves Up-Regulation of the Telomerase Catalytic Subunit and Telomere Elongation. Sensitivity of Resistant Cells to Combination Treatment with a Telomerase Inhibitor Mol. Pharmacol., November 1, 2003; 64(5): 1101 - 1108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-Y. Kim, M. Gleason-Guzman, E. Izbicka, D. Nishioka, and L. H. Hurley The Different Biological Effects of Telomestatin and TMPyP4 Can Be Attributed to Their Selectivity for Interaction with Intramolecular or Intermolecular G-Quadruplex Structures Cancer Res., June 15, 2003; 63(12): 3247 - 3256. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Kim, J. H. Kim, G. E. Lee, J. E. Lee, and I. K. Chung Potent Inhibition of Human Telomerase by Nitrostyrene Derivatives Mol. Pharmacol., May 1, 2003; 63(5): 1117 - 1124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Perez, L. R. Kelland, E. I. Montero, F. E. Boxall, M. A. Fuertes, C. Alonso, and C. Navarro-Ranninger Antitumor and Cellular Pharmacological Properties of a Novel Platinum(IV) Complex: trans-[PtCl2(OH)2(Dimethylamine) (Isopropylamine)] Mol. Pharmacol., April 1, 2003; 63(4): 933 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Maser and R. A. DePinho Connecting Chromosomes, Crisis, and Cancer Science, July 26, 2002; 297(5581): 565 - 569. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
