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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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Effect of one cycle of CPT-11 27 mg kg−1 day−1 × 5. Passage 1 (P1 – sensitive tumour) and passage 8 (P8 – resistant tumour): treatment discontinued in passage 8 (P8). P8P6 and P8P15: resistance verified in vivo at P8P6 (P6=6 passages without treatment after passage 8 with treatment); P8P15 (P15=15 passages without treatment after passage 8 with treatment). Central bars: medians.
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fig2: Effect of one cycle of CPT-11 27 mg kg−1 day−1 × 5. Passage 1 (P1 – sensitive tumour) and passage 8 (P8 – resistant tumour): treatment discontinued in passage 8 (P8). P8P6 and P8P15: resistance verified in vivo at P8P6 (P6=6 passages without treatment after passage 8 with treatment); P8P15 (P15=15 passages without treatment after passage 8 with treatment). Central bars: medians.

Mentions: In order to evaluate the stability of the resistance acquired, IGR-NB8-R tumours at passage 8 were further grown without treatment, while the prolonged treatment process was continued in parallel up to 28 passages. Sensitivity to CPT-11 was checked regularly (every 3–4 passages) by evaluating the TGD after one cycle (27 mg kg−1 × 5) of treatment. As shown in Figure 2Figure 2


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)

Effect of one cycle of CPT-11 27 mg kg−1 day−1 × 5. Passage 1 (P1 – sensitive tumour) and passage 8 (P8 – resistant tumour): treatment discontinued in passage 8 (P8). P8P6 and P8P15: resistance verified in vivo at P8P6 (P6=6 passages without treatment after passage 8 with treatment); P8P15 (P15=15 passages without treatment after passage 8 with treatment). Central bars: medians.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Effect of one cycle of CPT-11 27 mg kg−1 day−1 × 5. Passage 1 (P1 – sensitive tumour) and passage 8 (P8 – resistant tumour): treatment discontinued in passage 8 (P8). P8P6 and P8P15: resistance verified in vivo at P8P6 (P6=6 passages without treatment after passage 8 with treatment); P8P15 (P15=15 passages without treatment after passage 8 with treatment). Central bars: medians.
Mentions: In order to evaluate the stability of the resistance acquired, IGR-NB8-R tumours at passage 8 were further grown without treatment, while the prolonged treatment process was continued in parallel up to 28 passages. Sensitivity to CPT-11 was checked regularly (every 3–4 passages) by evaluating the TGD after one cycle (27 mg kg−1 × 5) of treatment. As shown in Figure 2Figure 2

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