Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II.

Tewey, K. M.; Chen, G. L.; Nelson, Eric M.; Liu, Leroy F.

doi:10.1016/s0021-9258(17)47282-6

Cited by 626 publications

(89 citation statements)

References 24 publications

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“…In our recent study of LMP517, we also noticed the ability of LMP517 to intercalate into DNA at high concentration as it has been previously established for LMP744 (36). This intercalating effect of LMP517 and LMP744 may explain the inhibitory effect on TOP2 as several chemical classes of DNA intercalating agents effectively trap TOP2ccs (45)(46)(47) by stacking with the base pairs flanking the TOP2cc, including the clinically used anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin), mitoxantrone, and amsacrine, as well as ellipticine derivatives (6,43). Indeed, DNA intercalation of drugs and ligands such as benzo[a]pyrene carcinogens at a TOP2 cleavage site can directly block the DNA religation by TOP2 (7,48,49).…”

Section: Discussionsupporting

confidence: 72%

The Indenoisoquinoline LMP517: A Novel Antitumor Agent Targeting both TOP1 and TOP2

Marzi

Sun

Huang

et al. 2020

Molecular Cancer Therapeutics

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The camptothecin derivatives topoisomerase I (TOP1) inhibitors, irinotecan and topotecan, are FDA approved for the treatment of colorectal, ovarian, lung and breast cancers. Because of the chemical instability of camptothecins, short plasma half-life, drug efflux by the multidrug-resistance ABC transporters, and the severe diarrhea produced by irinotecan, indenoisoquinoline TOP1 inhibitors (LMP400, LMP776, and LMP744), which overcome these limitations, have been developed and are in clinical development. Further modifications of the indenoisoquinolines led to the fluoroindenoisoquinolines, one of which, LMP517, is the focus of this study. LMP517showed better antitumor activity than its parent compound LMP744 against H82 (small cell lung cancer) xenografts. Genetic analyses in DT40 cells showed a dual TOP1 and TOP2 signature with selectivity of LMP517 for DNA repair-deficient tyrosyl DNA phosphodiesterase 2 (TDP2)-and Ku70-knockout cells. RADAR assays revealed that LMP517, and to a lesser extent LMP744, induce TOP2 cleavage complexes (TOP2cc) in addition to TOP1ccs. Histone gH2AX detection showed that, unlike classical TOP1 inhibitors, LMP517 targets cells independently of their position in the cell cycle. Our study establishes LMP517 as a dual TOP1 and TOP2 inhibitor with therapeutic potential.

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Section: Discussionsupporting

confidence: 72%

The Indenoisoquinoline LMP517: A Novel Antitumor Agent Targeting both TOP1 and TOP2

Marzi

Sun

Huang

et al. 2020

Molecular Cancer Therapeutics

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“…At very high concentrations of compound, the level of cleavage may be below that observed in the absence of drug. The most likely explanation for this pattern of responses is that high levels of compound intercalated in DNA completely block cleavage (Tewey et al, 1984). Thus, it is important that a wide range of compound concentrations be tested when examining an unknown agent for its ability to increase the levels of cleavage complexes.…”

Section: Critical Parameters and Troubleshootingmentioning

confidence: 99%

Topoisomerase Assays

et al. 2012

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Topoisomerases are nuclear enzymes that play essential roles in DNA replication, transcription, chromosome segregation, and recombination. All cells have two major forms of topoisomerases: type I, which makes single-stranded cuts in DNA, and type II enzymes, which cut and pass double-stranded DNA. DNA topoisomerases are important targets of approved and experimental anti-cancer agents. The protocols described in this unit are of assays used to assess new chemical entities for their ability to inhibit both forms of DNA topoisomerase. Included are an in vitro assay for topoisomerase I activity based on relaxation of supercoiled DNA and an assay for topoisomerase II based on the decatenation of double-stranded DNA. The preparation of mammalian cell extracts for assaying topoisomerase activity is described, along with a protocol for an ICE assay for examining topoisomerase covalent complexes in vivo and an assay for measuring DNA cleavage in vitro.

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“…Cyclophosphamide is an alkylating agent that acts by cross-linking DNA double strands and interferes with DNA replication (S phase) [ 18 ]. Doxorubicin is an antitumour antibiotic with a multi-modal mechanism of cellular toxicity that includes the inhibition of RNA and DNA polymerases and topoisomerase II, DNA intercalation and alkylation, and reactive oxygen species generation [ 19 , 20 , 21 ]. Although doxorubicin is thought to be cell-cycle non-specific, it functions most effectively during the S phase [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

L-Asparaginase, Doxorubicin, Vincristine, and Prednisolone (LHOP) Chemotherapy as a First-Line Treatment for Dogs with Multicentric Lymphoma

Lee

Liao

Wang

2021

Animals

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Cyclophosphamide exhibits the weakest therapeutic effect compared with vincristine and doxorubicin in the CHOP (C, cyclophosphamide; H, doxorubicin; O, vincristine; and P, prednisolone) chemotherapeutic protocol for the treatment of canine lymphoma. Twenty dogs with multicentric lymphoma were treated using the LHOP protocol, which used l-asparaginase in place of cyclophosphamide, and the outcomes were historically compared with those of dogs that received CHOP chemotherapy in the same institution. No significant differences were found in age (p = 0.107), body weight (p = 0.051), sex (p = 0.453), clinical stage V (p = 1), substage b (p = 0.573), T-cell phenotype (p = 0.340), overall response (p = 1), and hypercalcaemia status (p = 1) between the LHOP and CHOP groups. The adverse effects of l-asparaginase were well tolerated and self-limiting. The median PFS (progression-free survival) and median ST (survival time) in the LHOP group were 344 days (range: 28–940 days) and 344 days (range: 70–940 days), respectively. The median PFS and median ST in the CHOP group were 234 days (range: 49–1822 days) and 314 days (range: 50–1822 days), respectively. The dogs that received LHOP chemotherapy had a significantly longer PFS than the dogs that received CHOP chemotherapy (p = 0.001). No significant difference was observed in ST between the LHOP and CHOP groups (p = 0.131). Our study findings thus indicate that the LHOP protocol can be used as a first-line chemotherapeutic protocol in canine multicentric lymphoma.

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Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II.

Cited by 626 publications

References 24 publications

The Indenoisoquinoline LMP517: A Novel Antitumor Agent Targeting both TOP1 and TOP2

The Indenoisoquinoline LMP517: A Novel Antitumor Agent Targeting both TOP1 and TOP2

Topoisomerase Assays

L-Asparaginase, Doxorubicin, Vincristine, and Prednisolone (LHOP) Chemotherapy as a First-Line Treatment for Dogs with Multicentric Lymphoma

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