ABCC1 p.Thr24Met
| Predicted by SNAP2: | A: D (63%), C: D (71%), D: D (85%), E: D (85%), F: D (85%), G: D (66%), H: D (85%), I: D (85%), K: D (85%), L: D (85%), M: D (85%), N: D (75%), P: D (59%), Q: D (75%), R: D (63%), S: N (61%), V: D (66%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, V: D, W: D, Y: D, |
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[hide] Vinflunine (20',20'-difluoro-3',4'-dihydrovinorelb... Invest New Drugs. 1998;16(1):3-17. Etievant C, Barret JM, Kruczynski A, Perrin D, Hill BT
Vinflunine (20',20'-difluoro-3',4'-dihydrovinorelbine), a novel Vinca alkaloid, which participates in P-glycoprotein (Pgp)-mediated multidrug resistance in vivo and in vitro.
Invest New Drugs. 1998;16(1):3-17., [PMID:9740539]
Abstract [show]
Vinflunine (VFL) is a novel derivative of vinorelbine (NVB, Navelbine), which has shown markedly superior antitumor activity to NVB, in various experimental animal models. To establish whether this new Vinca alkaloid participates in P-glycoprotein (Pgp)-mediated multidrug resistance (MDR), VFL-resistant murine P388 cells (P388/VFL) were established in vivo and used in conjunction with the well established MDR P388/ADR subline, to define the in vivo resistance profile for VFL. P388/VFL cells proved cross-resistant to drugs implicated in MDR (other Vinca alkaloids, doxorubicin, etoposide), but not to campothecin or cisplatin and showed an increased expression of Pgp, without any detectable alterations in topoisomerase II or in glutathione metabolism. The P388/ADR cells proved cross-resistant to VFL both in vivo and in vitro, and this VFL resistance was efficiently modulated by verapamil in vitro. Cellular transport experiments with tritiated-VFL revealed differential uptake by P388 sensitive and P388/ADR resistant cells, comparable with data obtained using tritiated-NVB. In various in vitro models of human MDR tumor cells, whilst full sensitivity was retained in cells expressing alternative non-Pgp-mediated MDR mechanisms, cross resistance was identified in Pgp-overexpressing cells. Differences were, however, noted in terms of the drug resistance profiles relative to the other Vinca, with tumor cell lines proving generally least cross-resistant to VFL. Overall, these results suggest that VFL, like other Vinca alkaloids, participates in Pgp-mediated MDR, with tumor cells selected for resistance to VFL overexpressing Pgp, yet MDR tumor cell lines proved generally less cross resistant to VFL relative to the other Vinca alkaloids.
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No. Sentence Comment
79 The T24 sensitive (T24S) parental and the resistant T24M subline [28] were obtained from Dr R. Kiss, Laboratory of Histology, Université Libre de Bel- gique, ULB (Brussels, Belgium).
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ABCC1 p.Thr24Met 9740539:79:52
status: NEW83 The less well-characterized T24M cells, selected for resistance to a cocktail of doxorubicin, NVB and DIAM 3 (an investigational alkylating compound [32]) has been described as expressing an increased level of Pgp [33].
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ABCC1 p.Thr24Met 9740539:83:28
status: NEW87 Cell culture conditions Parental and resistant human tumor cell lines were cultured in RPMI 1640 medium (Seromed, Poly- labo, Strasbourg, France) supplemented with 10% heat inactivated fetal calf serum (FCS, GIBCO, Cergy-Pontoise, France), except for T24S and T24M cells which were grown in MEM medium (GIBCO) supplemented with 5% FCS.
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ABCC1 p.Thr24Met 9740539:87:260
status: NEW92 Characteristics of the tumor resistant sublines studied in vitro and the culture conditions used Resistance phenotypea Tumor Selecting agent Seeding Resistance index Pgp MRP Topo II Cell line origin [maintenance density to selecting agent over- over- decreased concentration] [cells/ml] expression expression level P388/ADR [24,30] murine doxorubicin 4.0 × 104 66 + ± + leukemia [1 µM] CEM/VBL 1000 [25] human vinblastine 2.0 × 104 135 + nr - leukemia [1 µM] T24M [28,33] human DOX/NVB/DIAM3b 2.5 × 104 6/3600/50 + nr nr bladder ca.b [0.1/1/10 µg/ml] MCF7/200R [27,31] human doxorubicin 5.0 × 104 >222 + - + breast ca.
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ABCC1 p.Thr24Met 9740539:92:484
status: NEW185 The well-known Pgp-associated MDR sublines, CEM/VBL1000 and MCF7/200R and the less well-characterized T24M subline, all expressed definite cross-resistance to VFL, as they did to the three other tubulin-interacting agents tested.
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ABCC1 p.Thr24Met 9740539:185:102
status: NEW189 Furthermore, whilst the T24M cells showed a comparable high level of resistance to NVB (3600-fold) and to vincristine (3700- fold), these proved less cross resistant to vinblastine (1200-fold) and again were least resistant to VFL (840-fold).
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ABCC1 p.Thr24Met 9740539:189:24
status: NEW190 Overall, in this group of Pgp overexpressing human tumor cell lines, the T24M, and especially the MCF7/200R sublines proved consistently less cross-resistant to VFL compared with vinblastine, vin- Figure 4.
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ABCC1 p.Thr24Met 9740539:190:73
status: NEW198 Resistance indices for the different resistant cell lines Cell line Resistance Resistance indexa phenotype vinblastine vincristine vinorelbine vinflunine CEM/VBL1000 Pgp-MDR 135 1547 469 184 T24M Pgp-MDR 1200 3700 3600 840 MCF7/200R Pgp-MDR 684 2440 600 188 GLC4/ADR non Pgp-MDR 1 4 1 1 CEM/VM1 non Pgp-MDR 0.5 0.8 0.5 0.5 aResistance index = IC50 resistant cell line/IC50 sensitive cell line.
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ABCC1 p.Thr24Met 9740539:198:191
status: NEW