Effects of two distamycin-ellipticine hybrid molecules on topoisomerase I and II mediated DNA cleavage: relation to cytotoxicity

Riou, Jean‐François; Grondard, Lucile; Naudin, Annette; Bailly, Christian

doi:10.1016/0006-2952(95)00132-j

Cited by 15 publications

(10 citation statements)

References 14 publications

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“…Its characteristics differed from those of each of the parent compounds distamycin and ellipticine [72]. A closely-related bis-cationic compound, Distel 2 (20), was not a topo inhibitor.…”

Section: Ellipticine-distamycin Hybridsmentioning

confidence: 90%

Dual Topoisomerase I / II Inhibitors in Cancer Therapy

Denny¹,

Baguley

2003

CTMC

141

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While the majority of topoisomerase (topo) inhibitors show selectivity against either topo I or topo II, a small class of compounds can act against both enzymes. These can be divided into three classes. The first and largest class comprise drugs that bind to DNA by intercalation and include the clinically-evaluated acridine DACA, the benzopyridoindole intoplicine, the indenoquinolinone TAS-103, the benzophenazine XR11576, and the pyrazoloacridine NSC 366140. The second category comprises hybrid molecules, prepared by physically linking separate inhibitors of topo I and topo II, or by linking pure topo inhibitors to other DNA-interactive carriers. While several derivatives (e.g., camptothecin-epipodophyllotoxin and ellipticine-distamycin hybrids) have been prepared, there have been no detailed studies. The third category are less well defined as a structural class, but apparently recognize structural motifs that are present in both topo I and II enzymes. These include a series of benzoisoquinolinium quaternary salts such as NK 109, and more interestingly modified versions of classical topo I or topo II inhibitors; e.g., the modified camptothecin BN 80927 and the modified epipodophyllotoxin tafluposide (F-11782). There is as yet no detailed understanding of the factors that result in selective or dual inhibition, but structure-activity studies in several classes show that structural changes can influence topo I/II selectivity. DNA intercalation mode also appears to play a part. The basis for the high antitumor activity of some topo inhibitors is not yet understood but may depend on the complex pattern of activities that include both inhibition and poisoning of the two enzymes.

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“…Its characteristics differed from those of each of the parent compounds distamycin and ellipticine [72]. A closely-related bis-cationic compound, Distel 2 (20), was not a topo inhibitor.…”

Section: Ellipticine-distamycin Hybridsmentioning

confidence: 90%

Dual Topoisomerase I / II Inhibitors in Cancer Therapy

Denny¹,

Baguley

2003

CTMC

141

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“…The antitumour effect of several clinically used drugs (e.g., amsacrine, doxorubicin, actinomycin D, mitoxantrone ) is believed to result from their ability to bind DNA and to interfere with the catalytic activities of topos. Therefore, the group of Riou et al 69 studied a composite molecule containing a DNA -intercalating ellipticine chromophore linked to the DNA minor groove binder distamycin (Distel (1 + ) ) (Figure 6 ). To convert the sequence neutral ligand into a highly AT-specific DNA binder, a second positively charged tail was introduced onto the distamycin moiety (Distel (2 + ) ) (Figure 6 ) .…”

Section: Distamycin±ellipticine Hybridsmentioning

confidence: 99%

Dual topoisomerase I/II inhibitors

Gijn

Lendfers

Schellens

et al. 2000

J Oncol Pharm Pract

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Topoisomerase (topo) I and II are nuclear enzymes, which play a major role in the topological rearrangement of DNA during replication and transcription processes. In the course of years, many different agents have been found which can inhibit the topos and thereby exploit cytotoxicity, also against tumour cells. Selective inhibition of the topo I enzyme can, however, induce a reactive increase in topo II levels, and vice versa. This mechanism is associated with the development of drug resistance. Dual inhibition of both topo I and II may, theoretically, overcome this resistance problem. In this review, the most important and promising dual topo I/II inhibitors designed as anticancer agents will be discussed. Thus far, only the indolyl quinoline derivative TAS-103, the 7 H-benzo [ e] pyrido [4,3- b] indole derivative intoplicine, and the acridine derivative PZA have been shown to be dual topo inhibitors with high cytotoxicity.

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“…Nevertheless, the clinical success of the camptothecin series has established topoisomerase I as an important and commercially viable pharmacological target in cancer treatment. Thus, there is an active effort to develop additional topoisomerase I inhibitors with structures and properties distinct from the camptothecins, such as benzophenanthridine alkaloids (nitidine and fagaronine) (Wang LK, 1993), coralyne and its analogues (Wang LK, 1996), intoplicine (Abigerges et al, 1996), Gl147211C (Besterman et al, 1996;Gerrits et al, 1996), quinolines and quinoxalines (Deady et al, 1997), benzimidazoles (Kim et al, 1996), an ellipticine-distamycin hybrid (Riou et al, 1995), and others (Funabashi et al, 1994;Gupta et al, 1995;Meikle et al, 1995;Boege et al, 1996;Cummings et al, 1996;Funayama et al, 1996;Makhey et al, 1996;Ray et al, 1996Ray et al, , 1997Rodriguez-Campos et al, 1996;Xie et al, 1996;Spicer et al, 1997). This promising class of anticancer drugs also exhibits antiviral activity (Priel et al, 1991).…”

Section: Topoisomerase I Inhibitorsmentioning

confidence: 99%

Untitled

Parchment¹,

Pessina²

1998

Cytotechnology

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DNA topoisomerase I is a nuclear enzyme which catalyzes the conversion of the DNA topology by introducing single-strand breaks into the DNA molecule. This enzyme represents a novel and distinct molecule target for cancer therapy by antitopoisomerase drugs belonging to the campthotecin series of antineoplastics. As many tumors can acquire resistance to drug treatment and become refractary to the chemotherapy it is very important to investigate the mechanisms involved in such a drug resistance for circumventing the phenomenon. This article describes the role of topoisomerase I in cell functions and the methods used to assess its in vitro catalytic activity. It reviews the mechanisms of cytotoxicity of the most specific antitopoisomerase I drugs by considering also the phenomenon of drug resistance. Some factors useful to drive the future perspectives in the development of new topoisomerase I inhibitors are also evidenced and discussed.

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Effects of two distamycin-ellipticine hybrid molecules on topoisomerase I and II mediated DNA cleavage: relation to cytotoxicity

Cited by 15 publications

References 14 publications

Dual Topoisomerase I / II Inhibitors in Cancer Therapy

Dual Topoisomerase I / II Inhibitors in Cancer Therapy

Dual topoisomerase I/II inhibitors

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