Preclinical profile of antitumor activity of a novel hydrophilic camptothecin, ST1968

Pisano, Claudio; Cesare, Michelandrea De; Beretta, Giovanni Luca; Zuco, Valentina; Pratesi, Graziella; Penco, Sergio; Vesci, Loredana; Foderà, Rosanna; Ferrara, F; Guglielmi, Mario B.; Carminati, Paolo; Dallavalle, Sabrina; Morini, Gabriella; Merlini, Lucio; Orlandi, Augusto; Zunino, Franco

doi:10.1158/1535-7163.mct-08-0266

Cited by 29 publications

(17 citation statements)

References 31 publications

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“…efficacy in a wide range of well-tolerated doses [9]. In spite of its cytotoxic potency (higher than that of topotecan, Table 1 remains to be defined.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, the hydrophilic derivative namitecan ( Fig. 1) exhibit an excellent activity, superior to that of irinotecan and topotecan (TPT), against several tumor models, including slowly growing tumors [9,10]. To better understand the basis of the peculiar profile of ST1968, we have performed a comparative study of ST1968 and topotecan in a squamous cell carcinoma model selected for resistance to topotecan (A431/TPT).…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of ST1968 (namitecan) on a topotecan-resistant squamous cell carcinoma

Zuco¹,

Supino²,

Favini³

et al. 2010

Biochemical Pharmacology

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ST1968 (namitecan), a novel 7-modified hydrophilic camptothecin, was found to be effective against tumor models relatively resistant to topotecan and irinotecan. Based on this observation, this study was designed to investigate the cellular and antitumor effects of ST1968 in a subline of A431, squamous cell carcinoma, selected for resistance to topotecan (A431/TPT). This model was characterized by a slow growth rate, associated with down-regulation of EGFR and topoisomerase I. In contrast to other camptothecins (SN38 and gimatecan), ST1968 was able to overcome almost completely the resistance at cellular level. The cellular pharmacokinetics indicated a comparable accumulation and retention of ST1968 in sensitive and resistant cells, in spite of expression of the efflux transporter, P-glycoprotein, in resistant cells. The uptake and retention of topotecan was dramatically reduced in both tumor cell lines, but more evident in the resistant one. In contrast to topotecan, ST1968 retained an outstanding efficacy in vivo against the resistant tumor (A431/TPT). The results are consistent with the interpretation that ST1968 was able to overcome the most relevant mechanisms associated with the development of topotecan resistance (i.e., slow proliferation and target downregulation) owing to its peculiar pharmacokinetic behaviour.

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“…efficacy in a wide range of well-tolerated doses [9]. In spite of its cytotoxic potency (higher than that of topotecan, Table 1 remains to be defined.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Efficacy of ST1968 (namitecan) on a topotecan-resistant squamous cell carcinoma

Zuco¹,

Supino²,

Favini³

et al. 2010

Biochemical Pharmacology

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“…Histological analysis and immunohistochemistry were performed as reported (Marcellini et al, 2006;Pisano et al, 2008).…”

Section: Immunohistochemical Analysesmentioning

confidence: 99%

PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy

Salvati¹,

Scarsella²,

Porru³

et al. 2010

Oncogene

108

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New anti-telomere strategies represent important goals for the development of selective cancer therapies. In this study, we reported that uncapped telomeres, resulting from pharmacological stabilization of quadruplex DNA by RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino [4,3,2-kl]acridinium methosulfate), trigger specific recruitment and activation of poly-adenosine diphosphate (ADP) ribose polymerase I (PARP1) at the telomeres, forming several ADP-ribose polymers that co-localize with the telomeric repeat binding factor 1 protein and are inhibited by selective PARP(s) inhibitors or PARP1-specific small interfering RNAs. The knockdown of PARP1 prevents repairing of RHPS4-induced telomere DNA breaks, leading to increases in chromosome abnormalities and eventually to the inhibition of tumor cell growth both in vitro and in xenografts. More interestingly, the integration of a TOPO1 inhibitor on the combination treatment proved to have a high therapeutic efficacy ensuing a complete regression of the tumor as well as a significant increase in overall survival and cure of mice even when treatments started at a very late stage of tumor growth. Overall, this work reveals the unexplored link between the PARP1 and G-quadruplex ligands and demonstrates the excellent efficacy of a multicomponent strategy based on the use of PARP inhibitors in telomere-based therapy.

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“…Although ST1968 is less potent than other CPT derivatives such as active SN38, it showed remarkable activity against CPT-11-resistant tumour models and yeast cells transfected with mutant TOP1. 16 In 2008, another study from the same group identified a novel TOP1 inhibitor, topopyrone C, isolated from the fungi Phoma and Penicillium and successfully synthesized and modified it in vitro.…”

Section: Topoisomerase 1 Inhibitorsmentioning

confidence: 99%