A phase II study of irinotecan in children with relapsed or refractory neuroblastoma: A European cooperation of the Société Française d’Oncologie Pédiatrique (SFOP) and the United Kingdom Children Cancer Study Group (UKCCSG)

Vassal, Gilles; Giammarile, Francesco; Brooks, Mariel; Geoerger, Birgit; Couanet, D.; Michon, Jean; Stockdale, Elizabeth; Schell, Matthias; Geoffray, A.; Gentet, Jean‐Claude; Pichon, F.; Cisar, Laura A.; Assadourian, Sylvie; Morland, Bruce

doi:10.1016/j.ejca.2008.08.003

Cited by 36 publications

(34 citation statements)

References 27 publications

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“…Pictures are representative images. D and F, columns, mean value of VEGF and CD31 and MMP-2 and MMP-9 expressions; errors bars, 95% CI; n.s., not significant; *, P < 0.05; **, P < 0.01;***, P < 0.001. disease stabilization (29), or no objective response (6), as in treatment with the camptothecin analogue topotecan (5). When given in combination with other agents, camptothecin analogs have shown efficacy in preclinical neuroblastoma models (30,31) and in phase I clinical trials (32,33).…”

Section: Discussionmentioning

confidence: 99%

“…Camptothecin and its analogs irinotecan (CPT-11) and topotecan hold great promise in the treatment of neuroblastoma for several reasons (3)(4)(5)(6). First, they have impressive activity against neuroblastoma cell lines resistant to standard antineuroblastoma agents.…”

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confidence: 99%

“…Such limitations are major considerations in neuroblastoma patients who often undergo nephrectomy, who are treated with cardiotoxic (doxorubicin) and nephrotoxic (platinum compounds) agents, and who receive irradiation. Third, cytotoxicity occurs at relatively nonmyelosuppressive dosages, suggesting that they can be safely given with other anticancer drugs (5,6).…”

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confidence: 99%

“…On the other hand, CPT-11 has several limitations, such as the limited and variable conversion by endogenous enzymes to convert the prodrug (CPT-11) to the active form (SN38; no better than approximately 4% of the total drug), an interindividual variability in drug safety profile, the induction of diarrhea (associated, in part, with the parent molecule), and the limited antitumor activity as a single agent (7,8) including in the treatment of neuroblastoma (6). These limitations suggest that direct delivery of the prodrug SN-38 may improve the efficacy and/or safety of this compound.…”

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confidence: 99%

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Tumor Regression and Curability of Preclinical Neuroblastoma Models by PEGylated SN38 (EZN-2208), a Novel Topoisomerase I Inhibitor

Pastorino

Loi

Sapra

et al. 2010

Clinical Cancer Research

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Purpose: Treatment of neuroblastoma is successful in less than half of patients with high-risk disease. The antitumor activity of a water soluble pegylated SN38 drug conjugate, EZN-2208, was compared with CPT-11 (a prodrug for SN38) in preclinical models of human neuroblastoma.Experimental Design: The in vitro cytotoxicity of EZN-2208 was tested by counting trypan blue dyeand Annexin V-positive cells, whereas its therapeutic efficacy was evaluated, in terms of survival, and antitumor and antiangiogenic activities, in s.c. luciferase-transfected, pseudometastatic, and orthotopic neuroblastoma animal models.Results: EZN-2208 was about 100-fold more potent than CPT-11 in vitro, by inducing apoptosis/ necrosis and p53 expression and by reducing hypoxia-inducible factor (HIF)-1α/HIF-2α expression. EZN-2208 gave superior antitumor effects compared with CPT-11 in neuroblastoma xenografts. EZN-2208 treatment always resulted in lack of tumor detection at the end of trials whereas only small therapeutic effects were observed with CPT-11, as assessed by luciferase assay or tumor size, or even by staining histologic sections of tumors with antibodies recognizing neuroblastoma cells and cell proliferation. In a neuroblastoma model resistant to doxorubicin, cisplatin, vincristine, fenretinide, and topotecan, EZN-2208 induced 100% curability. It also blocked tumor relapse after topotecan-vincristine-doxorubicin combined treatment. Mechanistic experiments showed statistically significantly enhanced terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Histone H2ax staining as well as decreased vascular endothelial growth factor, CD31, matrix metalloproteinase (MMP)-2, and MMP-9 expression in tumors removed from EZN-2208-treated mice and radiating vessels invading the tumor implanted onto the chorioallantoic membranes.Conclusions: EZN-2208 should be considered a most promising novel antineuroblastoma agent. An ongoing phase I study in pediatric patients should identify the optimal dose for a phase II study.

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Section: Discussionmentioning

confidence: 99%

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Tumor Regression and Curability of Preclinical Neuroblastoma Models by PEGylated SN38 (EZN-2208), a Novel Topoisomerase I Inhibitor

Pastorino

Loi

Sapra

et al. 2010

Clinical Cancer Research

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“…CPT-11 and TPT are most commonly used in the treatment of colon, ovarian and small-cell lung cancer in Europe and America [3][4][5]. The outcome of recurrent and refractory NB treatment with CPT-11 and TPT has been found to be satisfactory [2,[6][7][8]. However, the high cost of these drugs has limited their clinical use in China.…”

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10-Hydroxycamptothecin induces apoptosis in human neuroblastoma SMS-KCNR cells through p53, cytochrome c and caspase 3 pathways

Zf¹,

Ym²,

Xj³

et al. 2016

neo

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Neuroblastoma (NB), the most common extracranial solid tumor in childhood, remains one of the most challenging types of cancer to treat. Therefore, the search for novel effective drugs for its treatment is essential. The present study used 10-hydroxycamptothecin (HCPT), which is a naturally occurring alkaloid anticancer agent extracted from the Chinese tree, Camptotheca acuminata, and has a strong anticancer activity in vitro and in vivo. HCPT is able to induce apoptosis in cells of various tumor types. However, few studies have been conducted on its efficacy in NB, and its apoptosis-inducing mechanism has not been elucidated. In the present study, the in vitro effects of HCPT on apoptosis in the human NB cell line, SMS-KCNR, and its underlying molecular mechanisms were investigated. Cell proliferation was measured by an MTT assay and apoptosis was measured using DAPI staining and flow cytometric analysis. In addition, western blot analysis was used to evaluate the apoptosis-associated signaling pathways. HCPT was observed to markedly inhibit cell proliferation and induce apoptosis in SMS-KCNR cells at a relatively low concentration (2.5-20 nM). DAPI staining revealed typical apoptotic feature, namely apoptotic body formation. The flow cytometric analysis revealed that the number of apoptotic cells increased from 20.89% (for 2.5 nM) to 97.66% (for 20 nM) following HCPT treatment for 48 h. Western blot analysis revealed that p53, cytoplasmic cytochrome c, cleaved caspase-3 and poly ADP-ribose polymerase (PARP) proteins were significantly upregulated, while the mitochondrial cytochrome c and pro-caspase-3 proteins were downregulated. However, the B-cell lymphoma 2 and Bcl-2-associated X proteins were unaffected. The results indicated that HCPT may inhibit proliferation and induce apoptosis in the SMS-KCNR cells. The possible mechanism of apoptosis induction is the p53-mediated mitochondrial apoptotic signaling pathway, which promotes cytochrome c release and induces apoptosis by activating caspase-3 and PARP. Our study provides experimental evidence for HCPT as a potent therapeutic drug in NB treatment.

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Neuroblastoma

Vaidya¹,

Pearson²

2010

Pediatric Hematology and Oncology

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A phase II study of irinotecan in children with relapsed or refractory neuroblastoma: A European cooperation of the Société Française d’Oncologie Pédiatrique (SFOP) and the United Kingdom Children Cancer Study Group (UKCCSG)

Cited by 36 publications

References 27 publications

Tumor Regression and Curability of Preclinical Neuroblastoma Models by PEGylated SN38 (EZN-2208), a Novel Topoisomerase I Inhibitor

Tumor Regression and Curability of Preclinical Neuroblastoma Models by PEGylated SN38 (EZN-2208), a Novel Topoisomerase I Inhibitor

10-Hydroxycamptothecin induces apoptosis in human neuroblastoma SMS-KCNR cells through p53, cytochrome c and caspase 3 pathways

Neuroblastoma

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