Topoisomerase I inhibitors: selectivity and cellular resistance

Pommier, ﻿Yves; Pourquier, Philippe; Urasaki, Yoshimasa; Wu, Jiaxi; Laco, Gary S.

doi:10.1054/drup.1999.0102

Cited by 158 publications

(145 citation statements)

References 70 publications

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“…This is especially the case when Top1 relaxes positive supercoiling [10]. Failure to reseal this normally transient break in the DNA results in the generation of a Top1-linked DNA single-strand break that can be transformed into a prolonged doublestranded break following collision of replication forks with the drug-stabilized cleavage complex [11][12][13][14]. In a similar manner, a number of naturally occurring DNA lesions, such as strand breaks [15], abasic sites, base mismatches, and certain oxidized or modified bases [16], have also been shown in vitro to physically block the Top1 religation reaction through the misalignment the 5′-hydroxyl with the tyrosyl-DNA phosphodiester backbone.…”

Section: The Formation Of Irreversible Top1 Cleavage Complexesmentioning

confidence: 99%

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Dexheimer¹,

Antony²,

Marchand³

et al. 2008

ACAMC

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Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a recently discovered enzyme that catalyzes the hydrolysis of 3′-phosphotyrosyl bonds. Such linkages form in vivo following the DNA processing activity of topoisomerase I (Top1). For this reason, Tdp1 has been implicated in the repair of irreversible Top1-DNA covalent complexes, which can be generated by either exogenous or endogenous factors. Tdp1 has been regarded as a potential therapeutic co-target of Top1 in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin and its clinically used derivatives. Thus, by reducing the repair of Top1-DNA lesions, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1 inhibitors provided there is a presence of genetic abnormalities related to DNA checkpoint and repair pathways. Human Tdp1 can also hydrolyze other 3′-end DNA alterations including 3′-phosphoglycolates and 3′-abasic sites indicating it may function as a general 3′-DNA phosphodiesterase and repair enzyme. The importance of Tdp1 in humans is highlighted by the observation that a recessive mutation in the human TDP1 gene is responsible for the inherited disorder, spinocerebellar ataxia with axonal neuropathy (SCAN1). This review provides a summary of the biochemical and cellular processes performed by Tdp1 as well as the rationale behind the development of Tdp1 inhibitors for anticancer therapy.

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Section: The Formation Of Irreversible Top1 Cleavage Complexesmentioning

confidence: 99%

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Dexheimer¹,

Antony²,

Marchand³

et al. 2008

ACAMC

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145

203

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“…The median activity of topoisomerase I in A2780 and 2780DX8 cells was similar and amounted to 1.3 u mg 71 nuclear protein (range 0.7 -2.7 u mg 71 ). The three regions of the topoisomerase I cDNA, already known to bear mutations responsible for camptothecin resistance (Gupta et al, 1995;Pommier et al, 1999) were analysed for changes in sequence when compared to the sequence found in A2780. No mutations were detected in the domains analysed (data not shown).…”

Section: Topoisomerase I Gene Protein and Activitymentioning

confidence: 99%

Induction of breast cancer resistance protein by the camptothecin derivative DX-8951f is associated with minor reduction of antitumour activity

et al. 2002

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DX-8951f (exatecan mesylate), a new water-soluble derivative of camptothecin, is currently being evaluated in phase II clinical trials. Resistance may be acquired when treating cancer patients with DX-8951f. Therefore, we selected a subline of the human ovarian cancer cell line A2780 for resistance against DX-8951f to investigate possible mechanisms of resistance. This DX-8951f-resistant subline, designated 2780DX8 (resistance factor=9.3), displayed a typical cross-resistance pattern including compounds, such as topotecan (resistance factor =34), SN-38 (resistance factor =47), mitoxantrone (resistance factor =59) and doxorubicin (resistance factor =2.9), which have previously been associated with the expression of breast cancer resistance protein. 2780DX8 cells did not show changes in the topoisomerase I gene, in topoisomerase I protein levels or catalytic activity. Overexpression of breast cancer resistance protein could be detected, both at the mRNA and protein level, while staining for Pgp, MRP1, or LRP was negative. GF120918, an inhibitor of breast cancer resistance protein, was able to reverse the DX-8951f-induced resistance in 2780DX8 cells. In vivo experiments in well-established 2780DX8 human tumour xenografts demonstrated that the growth inhibition induced by CPT-11 was more affected by breast cancer resistance protein expression than that of DX-8951f. These data indicate for the first time that DX-8951f is able to induce breast cancer resistance protein as a mechanism of resistance. Breast cancer resistance protein, however, results in only minor reduction of antitumour activity of DX-8951f which is an advantage over topotecan and CPT-11/SN-38.

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“…The antitumor activity of CPT and its derivatives have been well documented, although the molecular mechanism of their activity has not been fully understood. For now, Top1 has been shown to be the only cellular target of CPT by Top1-knockout yeast studies and single point mutagenesis (Eng et al, 1988;Nitiss and Wang 1988;Pommier et al, 1999); therefore, it is the covalently cleavable complex, rather than CPT alone, that leads to many downstream signaling cascades. CPT induces downregulation of Cdc25A, which potentiates the S and G 2 /M cell cycle checkpoints and prevents propagation of damaged DNA (Xiao et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53

et al. 2011

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Mixed lineage leukemia 5 (MLL5) has been implicated in multiple aspects of cell physiology, such as hematopoiesis, cell cycle control and chromatin regulatory network. In this study, we present evidence that MLL5 is involved in the camptothecin (CPT)-induced p53 activation. CPT promoted the degradation of MLL5 protein in a time-and dose-dependent manner in actively replicating cells. The downregulation of MLL5 led to phosphorylation of p53 at Ser392, which was abrogated by exogenous overexpression of MLL5. In MLL5-knockdown cells, p53 protein was stabilized and bound to DNA with higher affinity, leading to activation of downstream genes. Co-immunoprecipitation showed that MLL5 preferentially interacted with the tetramerized form of p53, and knockdown of MLL5 promoted chromatin accumulation of p53 tetramers, suggesting that the association of MLL5 with p53 may prevent the p53 tetramers from binding to the chromatin target sites. The role of MLL5 in CPT-induced p53 activation was conserved in developing zebrafish, where CPT downregulated zebrafish Mll5 protein, and the microinjection of zebrafish mll5 mRNA substantially blocked the CPT-induced apoptosis. In summary, our study proposed MLL5 as a novel component in the regulation of p53 homeostasis and a new cellular determinant of CPT.

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Topoisomerase I inhibitors: selectivity and cellular resistance

Cited by 158 publications

References 70 publications

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Induction of breast cancer resistance protein by the camptothecin derivative DX-8951f is associated with minor reduction of antitumour activity

Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53

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