Sequential modifications of topoisomerase I activity in a camptothecin-resistant cell line established by progressive adaptation

Madelaine, Isabelle; Prost, Sandrine; Naudin, Annette; Riou, G; Lavelle, François; Riou, Jean-François

doi:10.1016/0006-2952(93)90069-9

Cited by 56 publications

(26 citation statements)

References 15 publications

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“…Resistance to these CPT analogues has been attributed to reduced expression or reduced activity of topo I (Eng et al, 1990;Sugimoto et al, 1990;Madelaine et al, 1993;Fujimori et al, 1995) Multidrug resistance has been associated with an increased expression of P-gp and MRP1, yielding reduced intracellular accumulation of drugs. P-gp has been shown to be involved in resistance to TPT, as acquired resistance to TPT was accompanied by increased expression of P-gp and reduced accumulation .…”

Section: Discussionmentioning

confidence: 99%

“…Several topo I inhibitor resistant cell lines have been established (Andoh et al, 1987;Eng et al, 1990;Kanzawa et al, 1990;Sugimoto et al, 1990;Hendricks et al, 1992;Madelaine et al, 1993;Pantazis et al, 1994;Fujimori et al, 1995;Sorensen et al, 1995). The mechanism of resistance has often been ascribed to various topo I-related changes, e.g.…”

mentioning

confidence: 99%

“…The mechanism of resistance has often been ascribed to various topo I-related changes, e.g. (1) reduced topo I catalytic activity (Madelaine et al, 1993;Fujimori et al, 1995;Sorensen et al, 1995), (2) decreased formation of cleavable complexes (Madelaine et al, 1993;Fujimori et al, 1995), (3) decreased expression of topo I (Eng et al, 1990;Sugimoto et al, 1990) and (4) a point mutation or rearrangement of topo I genes (Andoh et al, 1987;Fujimori et al, 1995). Reduced accumulation of TPT, due to P-glycoprotein (Pgp) overexpression, has been reported to add to resistance to topo I inhibitors as well Mattern et al, 1993;Hasegawa et al, 1995).…”

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confidence: 99%

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Reduced cellular accumulation of topotecan: a novel mechanism of resistance in a human ovarian cancer cell line

Maliepaard²,

Nooter³

et al. 1998

Br J Cancer

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Summary In order to unravel possible mechanisms of clinical resistance to topoisomerase inhibitors, we developed a topotecan-resistant human IGROV-1 ovarian cancer cell line, denoted IGROVTlOOr, by stepwise increased exposure to topotecan (TPT). The IGROVT100r cell line was 29-fold resistant to TPT and strongly cross-resistant to . However, the IGROVTlOOr showed only threefold resistance to camptothecin (CPT). Remarkably, this cell line was 32-fold resistant to mitoxantrone, whereas no significant cross-resistance against other cytostatic drugs was observed. No differences in topoisomerase protein levels and catalytic activity as well as topoisomerase cleavable complex stabilization by CPT in the IGROV-1 and IGROVTIOOr cell lines were observed, indicating that resistance in the IGROVTlOOr cell line was not related to topoisomerase I-related changes. However, resistance in the resistant IGROVTlOOr cell line to accompanied by decreased accumulation of the drugs to approximately 15% and 36% of that obtained in IGROV-1 respectively. No reduced accumulation was observed for CPT. Notably, accumulation of TPT in the IGROV-1 cell line decreased under energy-deprived conditions, whereas the accumulation in the IGROVTlOOr cell line increased under these energy-deprived conditions. The efflux of TPT at 370C was very rapid in the IGROV-1 as well as the IGROVT100r cell line, resulting in 90% efflux within 20 min. Importantly, the efflux rates of TPT in the IGROV-1 and IGROVTlOOr cell lines were not significantly different and were shown to be independent on P-glycoprotein (P-gp) or multidrug resistance-associated protein (MRP). These results strongly suggest that the resistance of the IGROVTlOOr cell line to TPT and SN-38 is mainly caused by reduced accumulation. The reduced accumulation appears to be mediated by a novel mechanism, probably related to impaired energy-dependent uptake of these topoisomerase drugs.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Reduced cellular accumulation of topotecan: a novel mechanism of resistance in a human ovarian cancer cell line

Maliepaard²,

Nooter³

et al. 1998

Br J Cancer

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“…However, several camptothecin-resistant cell lines have been described. The most common feature associated with camptothecin resistance is a reduced topoisomerase I activity as a result of either a reduction in the content of the enzyme or a mutation in the enzyme which renders itself less sensitive to drug, or a combination of both (Andoh et al, 1987;Gupta et al, 1988;Eng et al, 1990;Kanzawa et al, 1990;Chang et al, 1991;Kubota et al, 1992;Tanizawa and Pommier, 1992;Madelaine et al, 1993). NYH/TPT therefore resembles camptothecin-resistant cells in reduction in target activity.…”

Section: Discussionmentioning

confidence: 99%

“…A major feature of resistance towards these agents is a reduced extractable topoisomerase I activity reflecting a reduced content of the enzyme. In addition, some camptothecin-resistant cell lines display an altered topoisomerase I which is resistant to inhibition of catalytic activity by camptothecin and is frequently associated with a point mutation of the topoisomerase I gene (Andoh et al, 1987;Gupta et al, 1988;Tan et al, 1989;Eng et al, 1990;Kanzawa et al, 1990;Sugimoto et al, 1990a;Chang et al, 1992;Kubota et al, 1992;Woessner et al, 1992;Madelaine et al, 1993). Cell lines with primary resistance to topotecan have not, to our knowledge, previously been described in detail.…”

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Characterisation of a human small-cell lung cancer cell line resistant to the DNA topoisomerase I-directed drug topotecan

Sørensen¹,

Sehested²,

Pb³

1995

Br J Cancer

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Summary Camptothecins are DNA topoisomerase I-directed anti-tumour drugs with a novel mechanism of action. Topotecan (TPT), a hydrophilic derivative of camptothecin, is currently undergoing phase II clinical trials in small-cell lung cancer (SCLC). Human SCLC OC-NYH cells were made more than 6-fold resistant to topotecan by stepwise drug exposure and resistance was stable for 70 passages without drug. NYH/TPT cells had half the topoisomerase I level and activity of wild-type cells. However, no difference in camptothecin or topotecan inhibition of topoisomerase I-mediated DNA relaxation was found, indicating that the enzyme itself was unchanged in the resistant cell. In NYH/TPT cells, topoisomerase IIa and P levels were increased approximately 2-fold. Accordingly, the topoisomerase II-directed drug etoposide (VP-16) induced an increased number of DNA single-strand breaks in NYH/TPT cells. However, sensitivity to different topoisomerase Il-targeting agents in NYH/TPT cells varied from increased to decreased, indicating a role for as yet unidentified factors acting on the pathway to cell death after topoisomerase TI-induced DNA damage has occurred. Of 20 anti-cancer agents tested, only hydroxyurea showed marked collateral hypersensitivity in NYH/TPT cells.

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Overcoming CPT-11 resistance by using a biscoclaurine alkaloid, cepharanthine, to modulate plasma trans-membrane potential

Aogi

Nishiyama²,

Kim

et al. 1997

Int. J. Cancer

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Sequential modifications of topoisomerase I activity in a camptothecin-resistant cell line established by progressive adaptation

Cited by 56 publications

References 15 publications

Reduced cellular accumulation of topotecan: a novel mechanism of resistance in a human ovarian cancer cell line

Reduced cellular accumulation of topotecan: a novel mechanism of resistance in a human ovarian cancer cell line

Characterisation of a human small-cell lung cancer cell line resistant to the DNA topoisomerase I-directed drug topotecan

Overcoming CPT-11 resistance by using a biscoclaurine alkaloid, cepharanthine, to modulate plasma trans-membrane potential

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