Topoisomerase I-Mediated Antiproliferative Activity of Enantiomerically Pure Fluorinated Homocamptothecins

Lavergne, Olivier; Demarquay, Danièle; Bailly, Christian; Lanco, Christophe; Rolland, Alain; Huchet, Marion; Coulomb, Hélène; Müller, Nicolai; Baroggi, N.; Cámara, José Ignacio Mayordomo; Breton, Christophe; Manginot, Eric; Cazaux, J.-B.; Bigg, D. C. H.

doi:10.1021/jm000129j

Cited by 70 publications

(28 citation statements)

References 15 publications

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“…Although Pgp is not implicated in resistance to hCPTs (Lavergne et al, 2000a;Larsen et al, 2001), hCPTs have been shown to be subject to transport by MRP1 (Chauvier et al, 2002) and ABCG2 . In addition, selection with CPTs usually results in overexpression of ABCG2 (Maliepaard et al, 1999;Kawabata et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Reduced Expression of DNA Topoisomerase I in SF295 Human Glioblastoma Cells Selected for Resistance to Homocamptothecin and Diflomotecan

Liao¹,

Robey²,

Guirouilh‐Barbat³

et al. 2007

Mol Pharmacol

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Homocamptothecins (hCPTs) are a novel class of topoisomerase I (Top1) inhibitors with enhanced chemical stability compared with the currently used camptothecin (CPT) analogs irinotecan and topotecan. The hCPT derivative diflomotecan (BN80915) is currently in clinical trials. We established two resistant human glioblastoma cell lines, SF295/hCPT50 and SF295/BN50, by stepwise exposure of the parental SF295 line to increasing concentrations of hCPT and BN80915, respectively. The two resistant cell lines were 15-to 22-fold resistant to hCPT and BN80915 as well as 7-to 27-fold crossresistant to other Top1 inhibitors, including CPT, topotecan, and the indenoisoquinolines MJ-III-65 (NSC 706744) and NSC 724998, but sensitive to the topoisomerase II inhibitors mitoxantrone and etoposide. Neither of the resistant cell lines displayed any detectable expression of the three major drug transporters P-glycoprotien, multidrug resistance-associated protein 1, or ATP-binding cassette, subfamily G (WHITE), member 2, as assessed by immunoblot or flow cytometry. Reduced expression of Top1 protein occurred at the transcriptional level in both of the resistant cell lines, consistent with the reduction of Top1 enzyme level as the major contribution to the resistance phenotype in SF295/ hCPT50 and SF295/BN50 cells. Treatment of the resistant cell lines with the histone deacetylase inhibitor depsipeptide or the DNA methyltransferase inhibitor 5-aza-2Ј-deoxycytidine alone or concomitantly did not result in re-expression of Top1. Our studies suggest that selection for resistance to hCPT or BN80915 is primarily related to reduced Top1 expression at the transcriptional level, resulting in reduced enzyme levels.Homocamptothecins (hCPTs) are a new class of camptothecin (CPT) derivatives. They are different from the conventional CPT in that they bear a seven-membered ␤-hydroxylactone ring instead of the naturally occurring six-membered ␣-hydroxylactone observed in CPT (see Fig. 1). hCPTs are therefore more stable than CPT derivatives (Lavergne et al., 2000a,b) that are readily hydrolyzed to the inactive carboxylate forms (for review, see Pommier, 2006). hCPT, like other CPT analogs, inhibits Top1 by stabilizing the covalent complex between Top1 and DNA, leading to enzyme-linked DNA strand breaks, also referred to as cleavage complexes (Pommier, 2006). Because of their increased chemical stability, hCPTs were expected to exert greater Top1 inhibition and antitumor efficacy than the current FDA-approved CPT analogs irinotecan and topotecan [for review, see Lavergne et al. (2000b);Pommier (2006)]. hCPTs showed very potent antitumor efficacy in many tumors, including brain glioblastoma mouse models. The fluorinated hCPT diflomotecan (BN80915) is one of the most active compounds in terms of antiproliferative activity in the hCPT series (Bailly et al., 1999;Lavergne et al., 2000b). BN80915 has been selected for further development as a highly active hCPT-based Top1

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Section: Discussionmentioning

confidence: 99%

Reduced Expression of DNA Topoisomerase I in SF295 Human Glioblastoma Cells Selected for Resistance to Homocamptothecin and Diflomotecan

Liao¹,

Robey²,

Guirouilh‐Barbat³

et al. 2007

Mol Pharmacol

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“…This modification decreases the rates of hydrolysis and conversion to the carboxylate and also prevents the reverse reaction, i.e., the conversion of the homocamptothecin carboxylate to lactone (Lavergne et al, 1998;Lesueur-Ginot et al, 1999). Interestingly, homocamptothecins are more potent Top1 inhibitors than camptothecins and retain potent antitumor activity (Lavergne et al, 1998(Lavergne et al, , 2000Bailly et al, 1999;Lansiaux et al, 2001;Larsen et al, 2001). A difluoro homocamptothecin derivative, difluoro-camptothecin (BN80915), whose Top1 and antitumor activity in model systems are greater than those of homocamptothecin (Lansiaux et al, 2001;Larsen et al, 2001), is being pursued for clinical development.…”

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confidence: 99%

ABCG2 Mediates Differential Resistance to SN-38 (7-Ethyl-10-hydroxycamptothecin) and Homocamptothecins

Bates

Medina-Pérez²,

Kohlhagen³

et al. 2004

J Pharmacol Exp Ther

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One activity potentially limiting the efficacy of camptothecin anticancer agents is their cellular efflux by the ATP-binding cassette half-transporter, ABCG2. Homocamptothecins are novel anticancer drugs that inhibit topoisomerase 1 with a greater potency than camptothecins. Homocamptothecins differ from camptothecins by their E-ring, which is seven-membered instead of the six-membered ring of camptothecins. We report herein that, like camptothecins, homocamptothecin and its difluoro derivative BN80915 are substrates for ABCG2. However, the resistance of three selected cell lines overexpressing wild-type or mutant ABCG2 to homocamptothecin or BN80915 was less than resistance to SN-38 (7-ethyl-10-hydroxycamptothecin), indicating that both the seven-membered E-ring present in homocamptothecin and the A-and B-ring modifications present in SN-38 are involved in substrate recognition by ABCG2. HEK-293 cells transfected with vectors encoding wild-type or mutant ABCG2 were found to be less resistant to both homocamptothecins than to SN-38. However, transfectants overexpressing mutant ABCG2 had relative resistance values for homocamptothecin and BN80915 4-to 14-fold higher than cells expressing wild-type ABCG2, suggesting that the gain of function resulting from mutation at amino acid 482, although not affecting SN-38, extends to the homocamptothecins. Resistance was reversed by the ABCG2 inhibitor fumitremorgin C. BN80915 was 17-fold more potent than SN-38 in wild-type ABCG2-transfected cells, suggesting that BN80915 has the potential to overcome ABCG2-related resistance to SN-38, the active metabolite of CPT-11 (irinotecan).

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“…The compound acts as a potent Topo I poison as expected for both CPT and hCPT analogs (12,29,30). BN80927 performs well in isolated enzyme assays but also on living cells.…”

Section: Discussionmentioning

confidence: 89%

Bn80927

Demarquay¹,

Huchet²,

Coulomb³

et al. 2004

Cancer Research

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Topoisomerase I-Mediated Antiproliferative Activity of Enantiomerically Pure Fluorinated Homocamptothecins

Cited by 70 publications

References 15 publications

Reduced Expression of DNA Topoisomerase I in SF295 Human Glioblastoma Cells Selected for Resistance to Homocamptothecin and Diflomotecan

Reduced Expression of DNA Topoisomerase I in SF295 Human Glioblastoma Cells Selected for Resistance to Homocamptothecin and Diflomotecan

ABCG2 Mediates Differential Resistance to SN-38 (7-Ethyl-10-hydroxycamptothecin) and Homocamptothecins

Bn80927

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