Molecular and Biological Determinants of the Cytotoxic Actions of Camptothecins: Perspective for the Development of New Topoisomerase I Inhibitors

Kohn, Kurt W.; Pommier, ﻿Yves

doi:10.1111/j.1749-6632.2000.tb07021.x

Cited by 69 publications

(30 citation statements)

References 38 publications

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“…We noticed that this loss of replication competence during the S phase is followed by a rapid accumulation of DSBs and GCRs and then cell death. It has been demonstrated that CPT can cause the collapse of replication forks (Kohn and Pommier, 2000;Strumberg et al, 2000). DSB generated from such fork collapse is believed to represent the main cytotoxic lesion induced by CPT and its derivatives (Pommier et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Recql5 Plays an Important Role in DNA Replication and Cell Survival after Camptothecin Treatment

Zhou

et al. 2009

MBoC

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Disruption of replication can lead to loss of genome integrity and increase of cancer susceptibility in mammals. Thus, a replication impediment constitutes a formidable challenge to these organisms. Recent studies indicate that homologous recombination (HR) plays an important role in suppressing genome instability and promoting cell survival after exposure to various replication inhibitors, including a topoisomerase I inhibitor, camptothecin (CPT). Here, we report that the deletion of RecQ helicase Recql5 in mouse ES cells and embryonic fibroblast (MEF) cells resulted in a significant increase in CPT sensitivity and a profound reduction in DNA replication after the treatment with CPT, but not other DNAdamaging agents. This CPT-induced cell death is replication dependent and occurs primarily after the cells had exited the first cell cycle after CPT treatment. Furthermore, we show that Recql5 functions nonredundantly with Rad51, a key factor for HR to protect mouse ES cells from CPT-induced cytotoxicity. These new findings strongly suggest that Recql5 plays an important role in maintaining active DNA replication to prevent the collapse of replication forks and the accumulation of DSBs in order to preserve genome integrity and to prevent cell death after replication stress as a result of topoisomerase I poisoning. INTRODUCTIONMammalian RecQ helicases share a high degree of homology with the RecQ helicase of Escherichia coli (Nakayama, 2002). These helicases have important roles in maintaining the integrity of the genomes and promoting cell survival in response to various types of genotoxic stress (Hickson, 2003). In addition, some of them have also been implicated in DNA replication (Oakley et al., 2002;Cheok et al., 2005). The only RecQ helicase in E. coli, RecQ, plays an important role in the recovery of genomic replication after DNA damage Hanawalt, 1999, 2001). In both budding yeast and fission yeast, there exist also just a single RecQ helicase. In both species, the RecQ helicase is involved in a number of DNA transaction processes, including repair, recombination and chromosome segregation (Hickson, 2003). Interestingly, these enzymes do not appear to be essential for processive DNA synthesis. Rather, they are required to prevent genomic instability by coordinating replication and recombination events at stalled replication forks (Lambert et al., 2007). Unlike unicellular organisms which have a single RecQ helicase, mammals possess a family of helicases encoded by five different genes, i.e., human RECQL, BLM, WRN, RECQL4, and RECQL5 (Hickson, 2003). Each of these five genes encodes one or multiple polypeptides with distinctive C-and/or N-terminal domains, suggesting that they have related but nonoverlapping functions.In particular, mutations in three of the five RecQ homologues, RECQL4, WRN, and BLM give rise to three distinct genomic instability and cancer-prone genetic disorders: Rothmund-Thomson, Werner, and Bloom syndromes, respectively (Ellis et al., 1995;Yu et al., 1996;Kitao et al., 1999). However, th...

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Section: Discussionmentioning

confidence: 99%

Recql5 Plays an Important Role in DNA Replication and Cell Survival after Camptothecin Treatment

Zhou

et al. 2009

MBoC

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“…Only the lactone form is active with respect to inhibition of topoisomerase I. In blood and uids at physiological pH, the α-hydroxy δ-lactone ring moiety hydrolyzes which leads to deactivation of CPTs [5]. The process of deactivation is accelerated in a solution containing albumin.…”

Section: Introductionmentioning

confidence: 99%

“…Camptothecins exist in two forms: lactone, stable at pH<5. 5, and open ring carboxylate, stable at pH>9 (Table I). Only the lactone form is active with respect to inhibition of topoisomerase I.…”

Section: Introductionmentioning

confidence: 99%

Determination of the Protein-Binding Properties of Camptothecins by Means of Optical Spectroscopy Methods

et al. 2014

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Optical spectroscopy methods are widely used in studies of drugs. The a nity of camptothecins anticancer agents to human serum albumin (HSA) was determined in this work. Camptothecins (CPTs) exist in two forms: active lactone and open ring inactive carboxylate. In blood, the hydrolysis process of lactone form occurs which leads to deactivation of CPTs. Research is being done on biophysical properties of synthesized CPT compounds, in particular on binding to albumin. The a nity to plasma proteins is an important determinant of stability of CPTs in blood. The following analogues of CPT were tested in this paper: irinotecan, SN-38, topotecan, and 9-amino camptothecin. Using the method of uorescence anisotropy measurement, the association constants of the studied compounds to HSA were determined. The authors attempted to determine the deactivation rate of topotecan in HSA solution using Principal Component Analysis and Factor Analysis of absorption spectra recorded during hydrolysis process of lactone form.

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“…DNA topoisomerases are nuclear enzymes essential for DNA replication, RNA transcription, chromosomal condensation and mitotic chromatid separation (Caron and Wang, 1993;Gupta et al, 1995;Kohn and Pommier, 2000). There are two major classes of topoisomerases, I and II, in eukaryotic cells.…”

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confidence: 99%

“…Topoisomerase II functions as a dimer and forms a doublestranded cleavage with each topoisomerase II molecule covalently bound to the 5 0 -terminus of a DNA nucleotide, producing a double-stranded break (Holm et al, 1985). Topoisomerase-targeted agents stabilise a transient covalent enzyme -DNA complex, which produces DNA strand cleavage and apoptosis (Kohn and Pommier, 2000). Preclinical study of the in vivo therapeutic effect of sequential combinations of topoisomerase I-and II-acting drugs in a murine tumour model system reveals that topoisomerase I mRNA and protein levels in the tumour decrease, whereas topoisomerase II mRNA and protein levels rise, after treatment with camptothecins (Eder et al, 1998) and topotecan (Liebes et al, 1998).…”

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confidence: 99%

A phase I clinical trial of continual alternating etoposide and topotecan in refractory solid tumours

et al. 2005

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The goal of this phase I study was to develop a novel schedule using oral etoposide and infusional topotecan as a continually alternating schedule with potentially optimal reciprocal induction of the nontarget topoisomerase. The initial etoposide dose was 15 mg m À2 b.i.d. days (D)1 -5 weeks 1,3,5,7,9 and 11, escalated 5 mg per dose per dose level (DL). Topotecan in weeks 2,4,6,8,10 and 12 was administered by 96 h infusion at an initial dose of 0.2 mg m À2 day À1 with a dose escalation of 0.1, then at 0.05 mg m À2 day À1 . Eligibility criteria required no organ dysfunction. Two dose reductions or delays were allowed. A total of 36 patients with a median age of 57 (22 -78) years, received a median 8 (2 -19) weeks of chemotherapy. At DL 6, dose-limiting toxicities consisted of grade 3 nausea, vomiting and intolerable fatigue. Three patients developed a line-related thrombosis or infection and one subsequently developed AML. There was no febrile neutropenia. There were six radiologically confirmed responses (18%) and 56% of patients demonstrated a response or stable disease, typically with only modest toxicity. Oral etoposide 35 mg m À2 b.i.d. D1 -5 and 1.8 mg m À2 96 h (total dose) infusional topotecan D8 -11 can be administered on an alternating continual weekly schedule for at least 12 weeks, with promising clinical activity.

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Molecular and Biological Determinants of the Cytotoxic Actions of Camptothecins: Perspective for the Development of New Topoisomerase I Inhibitors

Cited by 69 publications

References 38 publications

Recql5 Plays an Important Role in DNA Replication and Cell Survival after Camptothecin Treatment

Recql5 Plays an Important Role in DNA Replication and Cell Survival after Camptothecin Treatment

Determination of the Protein-Binding Properties of Camptothecins by Means of Optical Spectroscopy Methods

A phase I clinical trial of continual alternating etoposide and topotecan in refractory solid tumours

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