Topoisomerase I inhibitors: camptothecins and beyond

Pommier, ﻿Yves

doi:10.1038/nrc1977

Cited by 1,938 publications

(2,045 citation statements)

References 123 publications

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“…Conversely, C max was not associated with OS. This is consistent with the hypothesis that dividing cells are sensitive to chemotherapy; thus, prolonged duration of chemotherapy drug exposures allow a greater number of tumor cells to be affected 21. The observed association between C avg and t uSN38>thr with efficacy indicates a strong association between plasma and tumor concentrations.…”

Section: Discussionsupporting

confidence: 87%

Population Pharmacokinetics of Liposomal Irinotecan in Patients With Cancer

Adiwijaya

Kim

Làng

et al. 2017

Clin Pharma and Therapeutics

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Nanoliposomal irinotecan (nal‐IRI) is a liposomal formulation of irinotecan with a longer half‐life (t1/2), higher plasma total irinotecan (tIRI), and lower SN‐38 maximum concentration (C max) compared with nonliposomal irinotecan. Population pharmacokinetic (PK) analysis of nal‐IRI was performed for tIRI and total SN‐38 (tSN38) using patient samples from six studies. PK‐safety association was evaluated for neutropenia and diarrhea in 353 patients. PK‐efficacy association was evaluated from a phase III study in pancreatic cancer NAPOLI1. Efficacy was associated with longer duration of unencapsulated SN‐38 (uSN38) above a threshold and higher Cavg of tIRI, tSN38, and uSN38. Neutropenia was associated with uSN38 C max and diarrhea with tIRI C max. Baseline predictive factors were race, body surface area, and bilirubin. Analysis identified PK factors associated with efficacy, safety, and predictive baseline factors. The results support the benefit of nal‐IRI dose of 70 mg/m2 (free‐base; equivalent to 80 mg/m2 salt base) Q2W over 100 mg/m2 Q3W.

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Section: Discussionsupporting

confidence: 87%

Population Pharmacokinetics of Liposomal Irinotecan in Patients With Cancer

Adiwijaya

Kim

Làng

et al. 2017

Clin Pharma and Therapeutics

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“…The strikingly high level of TOP1 we observed in Purkinje neurons compared to other cerebellar neurons indicates that these cells have an elevated requirement for this enzyme, perhaps due to a high demand for ribosomal RNA synthesis. TOP1 can become covalently attached to the DNA, forming TOP1 cleavage complexes (TOP1ccs) [36], and many types of endogenous DNA modifications can cause TOP1ccs [37]. The observation that spinocerebellar ataxia with axonal neuropathy (SCAN1) results from mutations in the TDP1 gene [22], which encodes a protein involved in the repair of TOP1ccs [38,39] indicates the importance of repair of such complexes in preventing ataxia.…”

Section: The Mrn-complex and Topoisomerase I Are Also Concentrated Inmentioning

confidence: 99%

ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain

et al. 2007

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The genetic disease ataxia telangiectasia (AT) results from mutations in the ataxia telangiectasia mutated (ATM) gene. AT patients develop a progressive degeneration of cerebellar Purkinje neurons. Surprisingly, while ATM plays a criticial role in the cellular reponse to DNA damage, previous studies have localized ATM to the cytoplasm of rodent and human Purkinje neurons. Here we show that ATM is primarily localized to the nucleus in cerebellar Purkinje neurons in postmortem human brain tissue samples, although some light cytoplasmic ATM staining was also observed. No ATM staining was observed in brain tissue samples from AT patients, verifying the specificity of the antibody. We also found that antibodies against components of the Mre11/Rad50/Nbs1 (MRN) complex showed strong staining in Purkinje cell nuclei. However, while ATM is present in both the nucleoplasm and nucleolus, MRN proteins are excluded from the nucleolus. We also observed very high levels of topoisomerase 1 (TOP1) in the nucleus, and specifically the nucleolus, of human Purkinje neurons. Our results have direct implications for understanding the mechanisms of neurodegeneration in AT and AT-like disorder.

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“…In the presence of CPT, the cleavable complex is stabilized, causing inhibition of both DNA and RNA synthesis; prolonged exposure to CPT leads to DNA-strand breaks and cell cycle arrest (Ryan et al, 1991;Staker et al, 2002). CPT selectively kills S-phase cells, possibly due to the association of Top1 with DNA replication complexes (Pommier, 2006). The antitumor activity of CPT and its derivatives have been well documented, although the molecular mechanism of their activity has not been fully understood.…”

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: camptothecins and beyond

Cited by 1,938 publications

References 123 publications

Population Pharmacokinetics of Liposomal Irinotecan in Patients With Cancer

Population Pharmacokinetics of Liposomal Irinotecan in Patients With Cancer

ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain

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

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