G-quadruplex ligand RHPS4 potentiates the antitumor activity of camptothecins in preclinical models of solid tumors.
OBJECTIVE
The formation of G-quadruplex structures at telomeric DNA sequences blocks telomerase activity, offering an original strategy to design and develop new antitumor agents. The pentacyclic acridinium salt RHPS4 is one of the most effective and selective G4 ligands able to rapidly disrupt telomere architecture, resulting in apoptosis of cancer cells. Here, we studied the therapeutic index of RHPS4 and its integration with chemotherapeutics in preclinical model of solid tumors.


METHODS
The antitumoral activity of RHPS4 was evaluated on human xenografts of different histotypes and compared with that of standard antineoplastic agents. Moreover, the effect of RHPS4/chemotherapeutics combinations on cell survival was studied and the most favorable combination was evaluated on tumor-bearing mice.


RESULTS
RHPS4 was active in vivo as single agent and showed a high therapeutic efficacy when compared with conventional drugs. Moreover, RHPS4 had antitumoral activity in human melanoma xenografts inherently resistant to chemotherapy and exhibited antimetastatic activity. RHPS4 also showed a strong synergistic interaction with camptothecins and this effect was strictly dependent on the drug sequence employed. Treatment of mice with irinotecan followed by RHPS4 was able to inhibit and delay tumor growth and to increase mice survival.


CONCLUSIONS
Our data show that RHPS4 has a good pharmacodynamic profile and in combination therapy produces a strong antitumoral activity, identifying this drug as promising agent for clinical development.
Leonetti
Carlo
C
Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Roma, Italy.
Scarsella
Marco
M
Riggio
Giuseppe
G
Rizzo
Angela
A
Salvati
Erica
E
D'Incalci
Maurizio
M
Staszewsky
Lidia
L
Frapolli
Roberta
R
Stevens
Malcolm F
MF
Stoppacciaro
Antonella
A
Mottolese
Marcella
M
Antoniani
Barbara
B
Gilson
Eric
E
Zupi
Gabriella
G
Biroccio
Annamaria
A
D000166:Acridines / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage; D004357:Drug Synergism; D005260:Female; D054856:G-Quadruplexes / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
C438609:3,11-difluoro-6,8,13-trimethyl-8H-quino(4,3,2-kl)acridinium; D000166:Acridines; D000970:Antineoplastic Agents; D008024:Ligands; D002166:Camptothecin