Direct Translation of a Protracted Irinotecan Schedule From a Xenograft Model to a Phase I Trial in Children

Furman, Wayne L.; Stewart, Clinton F.; Poquette, Catherine A.; Pratt, Charles B.; Santana, Víctor M.; Zamboni, William C.; Bowman, Laura C.; Kindlen, Margaret; Hoffer, Fredrick A.; Meyer, William H.; Pappo, Alberto S.; Walter, Andrew W.; Houghton, Peter J.

doi:10.1200/jco.1999.17.6.1815

Cited by 209 publications

(176 citation statements)

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“…Furthermore, the survival of patients with advanced disease without N-myc amplification (o10 copies) is not much greater (Kaneko et al, 2002). Cytotoxic therapies (doxorubicin, cyclophosphamide, etoposide, irinotecan and cisplatin) still play a major role in neuroblastoma treatment (Furman et al, 1999;Thompson et al, 1999Thompson et al, , 2001Houghton and Santana, 2002;Castel and Canete, 2004;Donfrancesco et al, 2004). Bone marrow or peripheral blood stem cell transplants appear to have some value increasing relapse-free survival, at least in some studies (Matthay et al, 1999;Valteau-Couanet et al, 2000;Imaizumi et al, 2001;Goldsby and Matthay, 2004).…”

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confidence: 99%

Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

et al. 2007

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We have previously described the identification of a nucleoside analog transcriptional inhibitor ARC (4-amino-6-hydrazino-7-b-D-ribofuranosyl-7H-pyrrolo[2,3-d]-pyrimidine-5-carboxamide) that was able to induce apoptosis in cancer cell lines of different origin. Here, we report the characterization of ARC on a panel of neuroblastoma cell lines. We found that these cell lines were more than 10-fold sensitive to ARC than to the well-known nucleoside analog DRB (5,6-dichloro-1-b-Dribofuranosylbenzimidazole), and that ARC-induced apoptosis proceeds through mitochondrial injury. Also, we observed that ARC-mediated cell death was accompanied by caspase-3 cleavage and repression of antiapoptotic proteins such as Mcl-1 and survivin. Conversely, we found that overexpression of Mcl-1-protected neuroblastoma cell line NB-1691 from ARC-induced apoptosis. Furthermore, we found that while ARC inhibited the phosphorylation of Akt Ser-473 in multiple cancer cell lines, forced expression of myristoylated Akt promoted resistance to ARC-induced apoptosis in neuroblastoma cells. In addition, we observed that ARC was able to downregulate the protein levels of N-myc, a commonly amplified oncogene in neuroblastomas, and Akt protected N-myc from ARCinduced downregulation. These data suggest that ARC may antagonize different antiapoptotic pathways and induce apoptosis in neuroblastoma cells via multiple mechanisms. Overall, ARC could represent an attractive candidate for anticancer drug development against neuroblastomas.

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confidence: 99%

Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

et al. 2007

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“…Similar effects have been reported for the topoisomerase I inhibitor topotecan, which induced tumour regression and a significant tumour growth delay (TGD) in animals bearing NB xenografts (Vassal et al, 1997). CPT-11 is currently evaluated in children with NB using several doses and schedules, such as 600 mg m À2 every 3 weeks, 50 mg m À2 day À1 Â 5 every 3 week or 20 mg m À2 day À1 Â 5 weekly for 2 weeks in a row every 3 weeks (Furman et al, 1999;Blaney et al, 2001;Vassal et al, 2003a).…”

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confidence: 59%

No topoisomerase I alteration in a neuroblastoma model with in vivo acquired resistance to irinotecan

et al. 2004

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CPT-11 (irinotecan) is a DNA-topoisomerase I inhibitor with preclinical activity against neuroblastoma (NB) xenografts. The aim was to establish in vivo an NB xenograft resistant to CPT-11 in order to study the resistance mechanisms acquired in a therapeutic setting. IGR-NB8 is an immature NB xenograft with MYCN amplification and 1p deletion, which is sensitive to CPT-11. Athymic mice bearing advanced-stage subcutaneous tumours were treated with CPT-11 (27 mg kg À1 day À1 Â 5) every 21 days (1 cycle) for a maximum of four cycles. After tumour regrowth, a new in vivo passage was performed and the CPT-11 treatment was repeated. After the third passage, a resistant xenograft was obtained (IGRNB8-R). The tumour growth delay (TGD) was reduced from 115 at passage 1 to 40 at passage 4 and no complete or partial regression was observed. After further exposure to the drug, up to 28 passages, the resistant xenograft was definitively established with a TGD from 17 at passage 28. Resistant tumours reverted to sensitive tumours after 15 passages without treatment. IGR-NB8-R remained sensitive to cyclophosphamide and cisplatin and cross-resistance was observed with the topoisomerase I inhibitor topotecan. No quantitative or qualitative topoisomerase I modifications were observed. The level of expression of multidrug resistance 1 (MDR1), MDR-associated protein 1 (MRP1) and, breast cancer resistance protein, three members of the ATP-binding cassette transporter family was not modified over passages. Our results suggest a novel resistance mechanism, probably not involving the mechanisms usually observed in vitro.

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“…The prognosis for children diagnosed with high-risk neuroblastoma is poor, with 5-year survival less than 30% (152). Topotecan and irinotecan anti-tumor activity in neuroblastoma has been demonstrated in preclinical studies and phase I clinical trials, including studies in children with high-risk disease (64,66,70,71,17,76,153).…”

Section: Mrp4 and P-glycoprotein Confer Resistance To Topotecan In Nementioning

confidence: 99%

“…Irinotecan ( investigators also determined that the irinotecan and SN-38 systemic exposures associated with the minimum effective dose in xenograft models can also be achieved clinically in children with cancer (17). Furthermore, at systemic exposures tolerated in children (75) …”

Section: Irinotecanmentioning

confidence: 99%

“…The camptothecin analogs topotecan and irinotecan are emerging as useful components of neuroblastoma therapy (15,17) and are also substrates for ABC transporters (18). Therefore, the major focus of this dissertation will be to assess the role of ABC transporter expression in resistance to the cytotoxicity of topotecan and irinotecan in vitro, in vivo, and in children with neuroblastoma.…”

Section: Introductionmentioning

confidence: 99%

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The Role of Multi-Drug Resistance Associated Protein 4 and P-glycoprotein in Resistance of Neuroblastoma to Topotecan and Irinotecan

Turner¹

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Clinton Stewart for his guidance and support. I will always appreciate his patience, the numerous opportunities he has provided, and all of the time he has spent teaching me. iii Abstract High-risk neuroblastoma presents a significant therapeutic challenge because the 5-year survival rate remains less than 30% despite the use of surgery, multi-agent chemotherapy, radiation, and autologous bone marrow transplant. Novel therapeutic modalities are under development. The camptothecin analogs topotecan and irinotecan have been identified as successful cytotoxic agents. For topotecan, pharmacokinetically guided dosing to achieve a systemic exposure associated with preclinical anti-tumor activity in neuroblastoma xenograft models is feasible and has elicited favorable responses in children with high-risk neuroblastoma. However, some children with highrisk disease did not respond to the putatively effective topotecan systemic exposure.These children represent a subset of the disease intrinsically resistant to topotecan.Furthermore, mRNA expression of the adenosine triphosphate (ATP)-binding cassette (ABC) transporters P-glycoprotein (Pgp) and multidrug resistance associated protein 1 (MRP1), which efflux many drugs used in neuroblastoma therapy, has been implicated in poor outcome in neuroblastoma. Therefore, the purpose of our studies was to determine the role of ABC transport protein expression in neuroblastoma resistance to the camptothecin analogs topotecan and irinotecan. The results of the in vitro studies demonstrate that MRP4 and Pgp confer resistance to topotecan and SN-38. In the xenograft studies, MRP4 expression was associated with failure to respond to topotecan. However, this phenotype was not recapitulated in children treated with topotecan. These results may be confounded by small sample size and timing of sample acquisition. Further investigation of the role of ABC transporters in children with neuroblastoma who receive either topotecan or irinotecan may be warranted. In addition to the camptothecin analogs, patients will receive other drugs effluxed by the ABC transporters (e.g., doxorubicin, vincristine, etoposide, and cyclophosphamide). Therefore, analyzing ABC transporter expression by immunohistochemistry in diagnostic tumor specimens may help to select agents not subject to efflux by ABC transporters expressed in the tumor. However, eliminating drugs effluxed by ABC transporters from the treatment regimen creates a potential gap in therapy and may reduce drug intensity. Therefore, further rational design and development of drugs that evade ABC transporter-mediated efflux, and potentially other resistance mechanisms in neuroblastoma, is also warranted.

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Direct Translation of a Protracted Irinotecan Schedule From a Xenograft Model to a Phase I Trial in Children

Cited by 209 publications

References 37 publications

Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

No topoisomerase I alteration in a neuroblastoma model with in vivo acquired resistance to irinotecan

The Role of Multi-Drug Resistance Associated Protein 4 and P-glycoprotein in Resistance of Neuroblastoma to Topotecan and Irinotecan

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