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

Calvet L, Santos A, Valent A, Terrier-Lacombe MJ, Opolon P, Merlin JL, Aubert G, Morizet J, Schellens JH, Bénard J, Vassal G - Br. J. Cancer (2004)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Pharmacology and New Treatments in Cancer (UPRES EA 3535), Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France.

ABSTRACT
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(-1) day(-1) x 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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Amplification of MYCN oncogene by quantitative real-time PCR. IGR-NB8-R xenograft under exposure to irinotecan [•] at passages 1, 9 and 24; reverted IGR-NB8-R P8P16 [⧫] after 16 passages without treatment with irinotecan; IGR-NB8 xenograft grown in parallel to IGR-NB8-R [○] at P1, between P5–P15 and P33–P39. Each symbol represents one tumour.
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fig5: Amplification of MYCN oncogene by quantitative real-time PCR. IGR-NB8-R xenograft under exposure to irinotecan [•] at passages 1, 9 and 24; reverted IGR-NB8-R P8P16 [⧫] after 16 passages without treatment with irinotecan; IGR-NB8 xenograft grown in parallel to IGR-NB8-R [○] at P1, between P5–P15 and P33–P39. Each symbol represents one tumour.

Mentions: Neuroblastomas that overexpress MYCN due to amplification of the MYCN oncogene are aggressive tumours that become resistant to chemotherapy. High expression of MRP1 RNA has been reported to be associated with MYCN amplification and poor treatment outcomes (Norris et al, 1996). Analysis of the MYCN oncogene in IGR-NB8-R xenograft showed that in spite of very heterogeneous expression in a given passage, there was no major difference, between MYCN amplification at P1 (sensitive tumour), P9 (resistant tumour) and P8P16 (reverted tumour) exhibiting a median value of 26.5, 25, and 20 copies per haploid genome, respectively (Figure 5Figure 5


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

Calvet L, Santos A, Valent A, Terrier-Lacombe MJ, Opolon P, Merlin JL, Aubert G, Morizet J, Schellens JH, Bénard J, Vassal G - Br. J. Cancer (2004)

Amplification of MYCN oncogene by quantitative real-time PCR. IGR-NB8-R xenograft under exposure to irinotecan [•] at passages 1, 9 and 24; reverted IGR-NB8-R P8P16 [⧫] after 16 passages without treatment with irinotecan; IGR-NB8 xenograft grown in parallel to IGR-NB8-R [○] at P1, between P5–P15 and P33–P39. Each symbol represents one tumour.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2747712&req=5

fig5: Amplification of MYCN oncogene by quantitative real-time PCR. IGR-NB8-R xenograft under exposure to irinotecan [•] at passages 1, 9 and 24; reverted IGR-NB8-R P8P16 [⧫] after 16 passages without treatment with irinotecan; IGR-NB8 xenograft grown in parallel to IGR-NB8-R [○] at P1, between P5–P15 and P33–P39. Each symbol represents one tumour.
Mentions: Neuroblastomas that overexpress MYCN due to amplification of the MYCN oncogene are aggressive tumours that become resistant to chemotherapy. High expression of MRP1 RNA has been reported to be associated with MYCN amplification and poor treatment outcomes (Norris et al, 1996). Analysis of the MYCN oncogene in IGR-NB8-R xenograft showed that in spite of very heterogeneous expression in a given passage, there was no major difference, between MYCN amplification at P1 (sensitive tumour), P9 (resistant tumour) and P8P16 (reverted tumour) exhibiting a median value of 26.5, 25, and 20 copies per haploid genome, respectively (Figure 5Figure 5

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Pharmacology and New Treatments in Cancer (UPRES EA 3535), Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France.

ABSTRACT
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(-1) day(-1) x 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.

Show MeSH
Related in: MedlinePlus