Clinical use of topoisomerase I inhibitors in anticancer treatment

Rodríguez‐Galindo, Carlos; Radomski, Kristine M.; Stewart, Clinton F.; Furman, Wayne L.; Santana, Víctor M.; Houghton, Peter J.

doi:10.1002/1096-911x(20001001)35:4<385::aid-mpo1>3.0.co;2-e

Cited by 49 publications

(16 citation statements)

References 121 publications

(123 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TPT and CPT-11 have been approved for first and second line treatment of advanced colorectal cancer and second line treatment for ovarian cancer (7)(8)(9). As with most chemotherapeutics, these CPT analogs are administered in combination with other agents (10 -13).…”

mentioning

confidence: 99%

Platinated DNA Adducts Enhance Poisoning of DNA Topoisomerase I by Camptothecin

Waardenburg

Jong

Eijndhoven

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Camptothecins constitute a novel class of chemotherapeutics that selectively target DNA topoisomerase I (Top1) by reversibly stabilizing a covalent enzyme-DNA intermediate. This cytotoxic mechanism contrasts with that of platinum drugs, such as cisplatin, which induce inter-and intrastrand DNA adducts. In vitro combination studies using platinum drugs combined with Top1 poisons, such as topotecan, showed a schedule-dependent synergistic activity, with promising results in the clinic. However, whereas the molecular mechanism of these single agents may be relatively well understood, the mode of action of these chemotherapeutic agents in combination necessitates a more complete understanding. Indeed, we recently reported that a functional homologous recombination pathway is required for cispla- TPT and CPT-11 have been approved for first and second line treatment of advanced colorectal cancer and second line treatment for ovarian cancer (7-9). As with most chemotherapeutics, these CPT analogs are administered in combination with other agents (10 -13). Although the molecular mechanisms of single agents may be well understood, the combination of two or more agents often induces surprising interactions, which necessitates a more complete understanding of the cytotoxic lesions induced by such combinations for optimal efficacy. For example, in vitro combination experiments using platinum agents, such as cisplatin (cDDP), carboplatin, or oxaliplatin, with a Top1 poison, TPT or CPT-11, demonstrated a sequencedependent synergy in various human tumor cell lines (14 -16). The most cytotoxic sequence was a platinum drug followed by a Top1 poison. Moreover, chemotherapeutic regimens that combine TPT/CPT-11 with platinum drug are showing some promise in the clinic (see Refs. 17-19 and references therein). However, the lack of insight into the mechanism of synergy hampers the optimal design of clinical studies based on the combination of platinum drugs and Top1 poisons.We recently reported genetic evidence that homologous recombination (HR) is responsible for the synergistic cytotoxicity of certain drug/Top1 poison combinations (20). Indeed, a functional HR pathway was required for the synergistic activity of platinum or X-irradiation in combination with TPT yet acted to suppress the synergistic combination of 1-␤-D-arabinofuranosyl cytidine

show abstract

mentioning

confidence: 99%

Platinated DNA Adducts Enhance Poisoning of DNA Topoisomerase I by Camptothecin

Waardenburg

Jong

Eijndhoven

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…These enzymes also constitute the targets of clinically important anticancer and antibacterial agents (4)(5)(6). With human DNA topoisomerase I (Top1), camptothecin (CPT) analogues (topotecan and CPT-11) have shown remarkable antitumor activity against pediatric and adult malignancies (7). These agents poison Top1 by reversibly stabilizing the covalent enzyme-DNA complex, inducing S-phase-dependent cell lethality.…”

mentioning

confidence: 99%

Locking the DNA topoisomerase I protein clamp inhibits DNA rotation and induces cell lethality

Woo

Losasso²,

Guo³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Eukaryotic DNA topoisomerase I (Top1) is a monomeric protein clamp that functions in DNA replication, transcription, and recombination. Opposable ''lip'' domains form a salt bridge to complete Top1 protein clamping of duplex DNA. Changes in DNA topology are catalyzed by the formation of a transient phosphotyrosyl linkage between the active-site Tyr-723 and a single DNA strand. Substantial protein domain movements are required for DNA binding, whereas the tight packing of DNA within the covalent Top1-DNA complex necessitates some DNA distortion to allow rotation. To investigate the effects of Top1-clamp closure on enzyme catalysis, molecular modeling was used to design a disulfide bond between residues Gly-365 and Ser-534, to crosslink protein loops more proximal to the active-site tyrosine than the protein loops held by the Lys-369 -Glu-497 salt bridge. In reducing environments, Top1-Clamp was catalytically active. However, contrary to crosslinking the salt-bridge loops [Carey, J. D NA topoisomerases alter DNA topology by the concerted cleavage and religation of DNA strand(s) (reviewed in refs. 1-3). The nucleophilic attack of an active-site tyrosine on a phosphodiester DNA bond generates a phosphotyrosyl linkage, providing a transient protein-linked gate through which another DNA strand or duplex may pass. A second transesterification resolves the tyrosyl-DNA linkage to restore DNA integrity. DNA topoisomerases play critical roles in most DNA transactions, including DNA replication, transcription, and recombination, as well as chromosome segregation. These enzymes also constitute the targets of clinically important anticancer and antibacterial agents (4-6). With human DNA topoisomerase I (Top1), camptothecin (CPT) analogues (topotecan and CPT-11) have shown remarkable antitumor activity against pediatric and adult malignancies (7). These agents poison Top1 by reversibly stabilizing the covalent enzyme-DNA complex, inducing S-phase-dependent cell lethality.Type IB enzymes, including eukaryotic and vaccinia virus Top1, are distinct from other enzymes in that the active-site tyrosine becomes linked to a 3Ј-phosphoryl end, versus the 5Ј-phosphotyrosine bond formed by types IA and II enzymes (1-3). Crystallographic data indicate that the monomeric enzymes (types IA and IB) or the protein subunits that constitute the symmetrical halves of type II enzymes [DNA gyrase and DNA topoisomerase II (Top2)] form a protein clamp (1-3). Yet, type IB enzymes are again unique in that biochemical and structural data support a mechanism of DNA rotation, as opposed to the coordinated domain movements in types IA and II enzymes that are necessary for an enzyme-bridging mechanism (1, 3, 8).The conserved central domain of eukaryotic Top1 forms the protein clamp (Fig. 1). Subdomains I and II constitute the upper cap, which is connected by a flexible hinge to the bottom part of the clamp, subdomain III. Two extended ␣-helices connect the clamp core with the conserved C-terminal domain, containing the activesite tyrosine. Human Top1 struc...

show abstract

“…10,13 We used a higher dose of topotecan (median dose, 5.0 mg/m 2 per day) than has been previously reported in the literature. 15,16 We chose to use this pharmacokinetically guided dosing approach for topotecan on the basis of our preclinical 37 and clinical data. 23 This topotecan dosage and the resultant high level of systemic exposure to topotecan lactone were remarkably well tolerated with acceptable myelotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it is imperative to evaluate the economic and therapeutic impact of any new mobilizing regimen to determine its usefulness. 14 Topotecan, a new topoisomerase I inhibitor with prominent activity 15 against many malignancies in pediatric and adult patients, is being evaluated in several new treatment regimens for various tumors. [16][17][18][19] Our aim was to compare the efficacy, toxicity, and relative costs of intravenously administered topotecan and filgrastim and of filgrastim alone in mobilizing PBSCs.…”

mentioning

confidence: 99%

Topotecan–filgrastim combination is an effective regimen for mobilizing peripheral blood stem cells

Yeoh

Cunningham

Yee

et al. 2001

Bone Marrow Transplant

View full text Add to dashboard Cite

Summary:We compared the efficacy, toxicity, and cost of topotecan-filgrastim and filgrastim alone for mobilizing peripheral blood stem cells (PBSCs) in 24 consecutive pediatric patients with newly diagnosed medulloblastoma. PBSCs were mobilized with an upfront window of topotecan-filgrastim for 11 high-risk patients (residual tumor у1.5 cm 2 after resection; metastases limited to neuraxis) and with filgrastim alone for 13 average-risk patients. All patients subsequently underwent craniospinal irradiation and four courses of high-dose chemotherapy with stem cell rescue. Target yields of CD34

show abstract

Clinical use of topoisomerase I inhibitors in anticancer treatment

Cited by 49 publications

References 121 publications

Platinated DNA Adducts Enhance Poisoning of DNA Topoisomerase I by Camptothecin

Platinated DNA Adducts Enhance Poisoning of DNA Topoisomerase I by Camptothecin

Locking the DNA topoisomerase I protein clamp inhibits DNA rotation and induces cell lethality

Topotecan–filgrastim combination is an effective regimen for mobilizing peripheral blood stem cells

Contact Info

Product

Resources

About