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Yves Pommier - One of the best experts on this subject based on the ideXlab platform.

  • rationale for poly adp ribose polymerase parp inhibitors in combination therapy with Camptothecins or temozolomide based on parp trapping versus catalytic inhibition
    Journal of Pharmacology and Experimental Therapeutics, 2014
    Co-Authors: Junko Murai, Yiping Zhang, Joel Morris, Jiuping Ji, Shunichi Takeda, James H Doroshow, Yves Pommier
    Abstract:

    We recently showed that poly(ADP-ribose) polymerase (PARP) inhibitors exert their cytotoxicity primarily by trapping PARP-DNA complexes in addition to their NAD+-competitive catalytic inhibitory mechanism. PARP trapping is drug-specific, with olaparib exhibiting a greater ability than veliparib, whereas both compounds are potent catalytic PARP inhibitors. Here, we evaluated the combination of olaparib or veliparib with therapeutically relevant DNA-targeted drugs, including the topoisomerase I inhibitor Camptothecin, the alkylating agent temozolomide, the cross-linking agent cisplatin, and the topoisomerase II inhibitor etoposide at the cellular and molecular levels. We determined PARP-DNA trapping and catalytic PARP inhibition in genetically modified chicken lymphoma DT40, human prostate DU145, and glioblastoma SF295 cancer cells. For Camptothecin, both PARP inhibitors showed highly synergistic effects due to catalytic PARP inhibition, indicating the value of combining either veliparib or olaparib with topoisomerase I inhibitors. On the other hand, for temozolomide, PARP trapping was critical in addition to catalytic inhibition, consistent with the fact that olaparib was more effective than veliparib in combination with temozolomide. For cisplatin and etoposide, olaparib only showed no or a weak combination effect, which is consistent with the lack of involvement of PARP in the repair of cisplatin- and etoposide-induced lesions. Hence, we conclude that catalytic PARP inhibitors are highly effective in combination with Camptothecins, whereas PARP inhibitors capable of PARP trapping are more effective with temozolomide. Our study provides insights in combination treatment rationales for different PARP inhibitors.

  • defective mre11 dependent activation of chk2 by ataxia telangiectasia mutated in colorectal carcinoma cells in response to replication dependent dna double strand breaks
    Journal of Biological Chemistry, 2006
    Co-Authors: H Takemura, Olivier Sordet, Takahisa Furuta, Ling Hua Meng, Hongliang Zhang, Zehong Miao, Yves Pommier
    Abstract:

    Abstract The Mre11·Rad50·Nbs1 (MRN) complex binds DNA double strand breaks to repair DNA and activate checkpoints. We report MRN deficiency in three of seven colon carcinoma cell lines of the NCI Anticancer Drug Screen. To study the involvement of MRN in replication-mediated DNA double strand breaks, we examined checkpoint responses to Camptothecin, which induces replication-mediated DNA double strand breaks after replication forks collide with topoisomerase I cleavage complexes. MRN-deficient cells were deficient for Chk2 activation, whereas Chk1 activation was independent of MRN. Chk2 activation was ataxia telangiectasia mutated (ATM)-dependent and associated with phosphorylation of Mre11 and Nbs1. Mre11 complementation in MRN-deficient HCT116 cells restored Chk2 activation as well as Rad50 and Nbs1 levels. Conversely, Mre11 down-regulation by small interference RNA (siRNA) in HT29 cells inhibited Chk2 activation and down-regulated Nbs1 and Rad50. Proteasome inhibition also restored Rad50 and Nbs1 levels in HCT116 cells suggesting that Mre11 stabilizes Rad50 and Nbs1. Chk2 activation was also defective in three of four MRN-proficient colorectal cell lines because of low Chk2 levels. Thus, six of seven colon carcinoma cell lines from the NCI Anticancer Drug Screen are functionally Chk2-deficient in response to replication-mediated DNA double strand breaks. We propose that Mre11 stabilizes Nbs1 and Rad50 and that MRN activates Chk2 downstream from ATM in response to replication-mediated DNA double strand breaks. Chk2 deficiency in HCT116 is associated with defective S-phase checkpoint, prolonged G2 arrest, and hypersensitivity to Camptothecin. The high frequency of MRN and Chk2 deficiencies may contribute to genomic instability and therapeutic response to Camptothecins in colorectal cancers.

  • topoisomerase i inhibitors Camptothecins and beyond
    Nature Reviews Cancer, 2006
    Co-Authors: Yves Pommier
    Abstract:

    Nuclear DNA topoisomerase I (TOP1) is an essential human enzyme. It is the only known target of the alkaloid Camptothecin, from which the potent anticancer agents irinotecan and topotecan are derived. As Camptothecins bind at the interface of the TOP1-DNA complex, they represent a paradigm for interfacial inhibitors that reversibly trap macromolecular complexes. Several Camptothecin and non-Camptothecin derivatives are being developed to further increase anti-tumour activity and reduce side effects. The mechanisms and molecular determinants of tumour response to TOP1 inhibitors are reviewed, and rational combinations of TOP1 inhibitors with other drugs are considered based on current knowledge of repair and checkpoint pathways that are associated with TOP1-mediated DNA damage.

  • p21cdkn1a allows the repair of replication mediated dna double strand breaks induced by topoisomerase i and is inactivated by the checkpoint kinase inhibitor 7 hydroxystaurosporine
    Oncogene, 2006
    Co-Authors: Takahisa Furuta, R L Hayward, Ling Hua Meng, Haruyuki Takemura, Gregory J Aune, William M Bonner, Mirit I Aladjem, Kurt W Kohn, Yves Pommier
    Abstract:

    This study provides evidence for the importance of p21 CDKN1A for the repair of replication-mediated DNA double-strand breaks (DSBs) induced by topoisomerase I. We report that defects of p21 CDKN1A and p53 enhance Camptothecin-induced histone H2AX phosphorylation (yH2AX), a marker for DNA DSBs. In human colon carcinoma HCT116 cells with wild-type (wt) p53, yH2AX reverses after Camptothecin removal. By contrast, yH2AX increases after Camptothecin removal in HCT116 cells deficient for p53 (p53-/-) or p21 CDKN1A (p21-/-) as the cells reach the late-S and G2 phases. Since p21-/- cells exhibit similar S-phase arrest as wt cells in response to Camptothecin and aphidicolin does not abrogate the enhanced yH2AX formation in p21-/- cells, we conclude that enhanced yH2AX formation in p21-/- cells is not due to re-replication. The cell cycle checkpoint abrogator and Chkl/Chk2 inhibitor 7-hydroxystaurosporine (UCN-01) also increases Camptothecin-induced yH2AX formation and inhibits Camptothecin-induced p21 CDKN1A upregulation in HCT116 wt cells. TUNEL (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling) assays demonstrate that yH2AX formation in late S and G2 cells following CPT treatment corresponds to DNA breaks. However, these breaks are not related to apoptotic DNA fragmentation. We propose that p21 CDKN1A prevents the collapse of replication forks damaged by stabilized topoisomerase I cleavage complexes.

  • molecular and biological determinants of the cytotoxic actions of Camptothecins perspective for the development of new topoisomerase i inhibitors
    Annals of the New York Academy of Sciences, 2006
    Co-Authors: Kurt W Kohn, Yves Pommier
    Abstract:

    : Camptothecin, originally discovered in 1957 as an antitumor activity in plant extracts, has recently become one of the most promising leads to new anticancer drugs. After lingering for many years, interest in Camptothecin was revitalized in 1985 upon discovery of its specific action on topoisomerase I. Detailed elucidation of action mechanisms at the molecular, cellular, and pharmacologic levels has made Camptothecin and its congeners perhaps the best understood among clinical anticancer drugs. Promising chemical variants of Camptothecin, and recently other chemical categories of topoisomerase I-targeted drugs, provide unusually rich opportunities for rational drug selection and design. This is made possible by current concepts based, for the most part, on a sound experimental foundation, which points the way towards optimally effective therapy.

Glenda Kohlhagen - One of the best experts on this subject based on the ideXlab platform.

  • abcg2 mediates differential resistance to sn 38 7 ethyl 10 hydroxyCamptothecin and homoCamptothecins
    Journal of Pharmacology and Experimental Therapeutics, 2004
    Co-Authors: Susan E Bates, Glenda Kohlhagen, Smitha Antony, Wilma Y Medinaperez, Tim Nadjem, Robert W Robey, Yves Pommier
    Abstract:

    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).

  • dual role of glutathione in modulating Camptothecin activity depletion potentiates activity but conjugation enhances the stability of the topoisomerase i dna cleavage complex
    Molecular Cancer Therapeutics, 2001
    Co-Authors: Michael P Gamcsik, Glenda Kohlhagen, Mansukh C Wani, Monroe E Wall, Mohit Kasibhatla, David J Adams, James L Flowers, Michael O Colvin, Govindarajan Manikumar, Yves Pommier
    Abstract:

    Depletion of glutathione (GSH) in MCF-7 and MDA-MB-231 cell lines by pretreatment with the GSH synthesis inhibitor buthionine sulfoximine potentiated the activity of 10,11-methylenedioxy-20( S )-Camptothecin, SN-38 [7-ethyl-10-hydroxy-20( S )-Camptothecin], topotecan, and 7-chloromethyl-10,11-methylenedioxy-20( S )-Camptothecin (CMMDC). The greatest potentiation was observed with the alkylating Camptothecin CMMDC. Buthionine sulfoximine pretreatment also increased the number of Camptothecin-induced DNA-protein cross-links, indicating that GSH affects the mechanism of action of Camptothecin. We also report that GSH interacts with CMMDC to form a stable conjugate, 7-(glutathionylmethyl)-10,11-methylenedioxy-20( S )-Camptothecin (GSMMDC), which is formed spontaneously in buffered solutions and in MCF-7 cells treated with CMMDC. GSMMDC was synthesized and found to be nearly as active as 10,11-methylenedioxy-20( S )-Camptothecin in a topoisomerase (topo) I-mediated DNA nicking assay. The resulting topo I cleavage complexes were remarkably stable. In cell culture, GSMMDC displayed potent growth-inhibitory activity against U937 and P388 leukemia cell lines. GSMMDC was not active against a topo I-deficient P388 cell line, indicating that topo I is its cellular target. Peptide-truncated analogues of GSMMDC were prepared and evaluated. All three derivatives [7-(γ-glutamylcysteinylmethyl)-10,11-methylenedioxy-20( S )-Camptothecin, 7-(cysteinylglycylmethyl)-10,11-methylenedioxy-20( S )-Camptothecin, and 7-(cysteinylmethyl)-10,11-methylenedioxy-20( S )-Camptothecin] displayed topo I and cell growth-inhibitory activity. These results suggest that 7-peptidyl derivatives represent a new class of Camptothecin analogues.

  • the novel silatecan 7 tert butyldimethylsilyl 10 hydroxyCamptothecin displays high lipophilicity improved human blood stability and potent anticancer activity
    Journal of Medicinal Chemistry, 2000
    Co-Authors: David Bom, Glenda Kohlhagen, Dennis P Curran, Stefan Kruszewski, Stephen G Zimmer, Thompson J Strode, Ashok J Chavan, Kimberly A Fraley, Alex L Bingcang, Lori J Latus
    Abstract:

    We describe the rational design and synthesis of B- and A,B-ring-modified Camptothecins. The key α-hydroxy-δ-lactone pharmacophore in 7-tert-butyldimethylsilyl-10-hydroxyCamptothecin (DB-67, 14) displays superior stability in human blood when compared with clinically relevant Camptothecin analogues. In human blood 14 displayed a t1/2 of 130 min and a percent lactone at equilibrium value of 30%. The tert-butyldimethylsilyl group renders the new agent 25-times more lipophilic than Camptothecin, and 14 is readily incorporated, as its active lactone form, into cellular and liposomal bilayers. In addition, the dual 7-alkylsilyl and 10-hydroxy substitution in 14 enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell lines derived from eight distinct tumor types indicate that 14 is of comparable potency to campt...

  • the novel silatecan 7 tert butyldimethylsilyl 10 hydroxyCamptothecin displays high lipophilicity improved human blood stability and potent anticancer activity
    Journal of Medicinal Chemistry, 2000
    Co-Authors: David Bom, Glenda Kohlhagen, Dennis P Curran, Stefan Kruszewski, Stephen G Zimmer, Thompson J Strode, Ashok J Chavan, Kimberly A Fraley, Alex L Bingcang, Lori J Latus
    Abstract:

    We describe the rational design and synthesis of B- and A, B-ring-modified Camptothecins. The key alpha-hydroxy-delta-lactone pharmacophore in 7-tert-butyldimethylsilyl-10-hydroxyCamptothecin (DB-67, 14) displays superior stability in human blood when compared with clinically relevant Camptothecin analogues. In human blood 14 displayed a t(1/2) of 130 min and a percent lactone at equilibrium value of 30%. The tert-butyldimethylsilyl group renders the new agent 25-times more lipophilic than Camptothecin, and 14 is readily incorporated, as its active lactone form, into cellular and liposomal bilayers. In addition, the dual 7-alkylsilyl and 10-hydroxy substitution in 14 enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell lines derived from eight distinct tumor types indicate that 14 is of comparable potency to Camptothecin and 10-hydroxyCamptothecin, as well as the FDA-approved Camptothecin analogues topotecan and CPT-11. In addition, cell-free cleavage assays reveal that 14 is highly active and forms more stable top1 cleavage complexes than Camptothecin or SN-38. The impressive blood stability and cytotoxicity profiles for 14 strongly suggest that it is an excellent candidate for additional in vivo pharmacological and efficacy studies.

  • Camptothecin resistance role of the atp binding cassette abc mitoxantrone resistance half transporter mxr and potential for glucuronidation in mxr expressing cells
    Cancer Research, 1999
    Co-Authors: Mariafiorella Brangi, Yves Pommier, Glenda Kohlhagen, Robert W Robey, Thomas Litman, Marco Ciotti, Kenryu Nishiyama, Chris H Takimoto, Tito Fojo, Susan E Bates
    Abstract:

    The mitoxantrone resistance (MXR) gene encodes a recently characterized ATP-binding cassette half-transporter that confers multidrug resistance. We studied resistance to the Camptothecins in two sublines expressing high levels of MXR: S1-M1-80 cells derived from parental S1 colon cancer cells and MCF-7 AdVp3000 isolated from parental MCF-7 breast cancer cells. Both cell lines were 400- to 1000-fold more resistant to topotecan, 9-amino-20(S)-Camptothecin, and the active metabolite of irinotecan, 7-ethyl-10-hydroxyCamptothecin (SN-38), than their parental cell lines. The cell lines demonstrated much less resistance to Camptothecin and to several Camptothecin analogues. Reduced accumulation and energy-dependent efflux of topotecan was demonstrated by confocal microscopy. A significant reduction in cleavable complexes in the resistant cells could be observed after SN-38 treatment but not after Camptothecin treatment. In addition to topotecan and SN-38, MXR-overexpressing cells are highly resistant to mitoxantrone and epirubicin. Because these compounds are susceptible to glucuronidation, we examined UDP-glucuronosyltransferase (UGT) activity in parental and resistant cells by TLC. Glucuronides were found at equal levels in both parental and resistant colon cancer cell lines for epirubicin and to a lesser extent for SN-38 and mitoxantrone. Low levels of glucuronidation could also be detected in the resistant breast cancer cells. These results were confirmed by analysis of the UGT1A family mRNAs. We thus conclude that colon and breast cancer cells have a capacity for glucuronidation that could contribute to intrinsic drug resistance in colon cancer cells and may be acquired in breast cancer cells. The lack of selection for higher levels of UGT capacity in the colon cells suggests that high levels of expression of MXR alone are sufficient to confer resistance to the Camptothecins.

Lori J Latus - One of the best experts on this subject based on the ideXlab platform.

  • the novel silatecan 7 tert butyldimethylsilyl 10 hydroxyCamptothecin displays high lipophilicity improved human blood stability and potent anticancer activity
    Journal of Medicinal Chemistry, 2000
    Co-Authors: David Bom, Glenda Kohlhagen, Dennis P Curran, Stefan Kruszewski, Stephen G Zimmer, Thompson J Strode, Ashok J Chavan, Kimberly A Fraley, Alex L Bingcang, Lori J Latus
    Abstract:

    We describe the rational design and synthesis of B- and A,B-ring-modified Camptothecins. The key α-hydroxy-δ-lactone pharmacophore in 7-tert-butyldimethylsilyl-10-hydroxyCamptothecin (DB-67, 14) displays superior stability in human blood when compared with clinically relevant Camptothecin analogues. In human blood 14 displayed a t1/2 of 130 min and a percent lactone at equilibrium value of 30%. The tert-butyldimethylsilyl group renders the new agent 25-times more lipophilic than Camptothecin, and 14 is readily incorporated, as its active lactone form, into cellular and liposomal bilayers. In addition, the dual 7-alkylsilyl and 10-hydroxy substitution in 14 enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell lines derived from eight distinct tumor types indicate that 14 is of comparable potency to campt...

  • the novel silatecan 7 tert butyldimethylsilyl 10 hydroxyCamptothecin displays high lipophilicity improved human blood stability and potent anticancer activity
    Journal of Medicinal Chemistry, 2000
    Co-Authors: David Bom, Glenda Kohlhagen, Dennis P Curran, Stefan Kruszewski, Stephen G Zimmer, Thompson J Strode, Ashok J Chavan, Kimberly A Fraley, Alex L Bingcang, Lori J Latus
    Abstract:

    We describe the rational design and synthesis of B- and A, B-ring-modified Camptothecins. The key alpha-hydroxy-delta-lactone pharmacophore in 7-tert-butyldimethylsilyl-10-hydroxyCamptothecin (DB-67, 14) displays superior stability in human blood when compared with clinically relevant Camptothecin analogues. In human blood 14 displayed a t(1/2) of 130 min and a percent lactone at equilibrium value of 30%. The tert-butyldimethylsilyl group renders the new agent 25-times more lipophilic than Camptothecin, and 14 is readily incorporated, as its active lactone form, into cellular and liposomal bilayers. In addition, the dual 7-alkylsilyl and 10-hydroxy substitution in 14 enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell lines derived from eight distinct tumor types indicate that 14 is of comparable potency to Camptothecin and 10-hydroxyCamptothecin, as well as the FDA-approved Camptothecin analogues topotecan and CPT-11. In addition, cell-free cleavage assays reveal that 14 is highly active and forms more stable top1 cleavage complexes than Camptothecin or SN-38. The impressive blood stability and cytotoxicity profiles for 14 strongly suggest that it is an excellent candidate for additional in vivo pharmacological and efficacy studies.

David Bom - One of the best experts on this subject based on the ideXlab platform.

  • a versatile prodrug approach for liposomal core loading of water insoluble Camptothecin anticancer drugs
    Journal of the American Chemical Society, 2002
    Co-Authors: Xinli Liu, David Bom, Dennis P Curran, Bert C Lynn, Junhong Zhang, Lin Song, Thomas G Burke
    Abstract:

    We describe a versatile prodrug strategy for loading the liposomal lumen with water-insoluble Camptothecins. The procedure involves conversion of an active Camptothecin analogue to a 20-OR omega-aminoalkanoanic ester prodrug in which R = CO[CH(2)](n)()NH(2) and n = 1-3. The basic amino group of the prodrug serves three roles. First, at pH ranges of 3-5, the amine enhances aqueous solubility. Second, it enhances responsiveness to a transmembrane ammonium sulfate gradient across the liposomal bilayer, thereby facilitating active loading of the agent into the liposomal aqueous core. Third, at a physiological pH of 7 or above (the pH to be encountered following drug release at the tumor site), the nucleophilicity of the amine manifests itself and cyclization to the C-21 carbonyl carbon occurs. This cyclization triggers a rapid and convenient nonenzymatic decomposition process that releases active Camptothecin. Accordingly, this novel liposomal approach offers a potential system for tumor-targeting prodrugs of many water-insoluble Camptothecins, including the highly lipophilic and clinically attractive analogues SN-38, 9-nitroCamptothecin and DB-67. The rate of formation of the active agent at the tumor site can be controlled through the selection of n (the length of the alkyl spacer group).

  • the novel silatecan 7 tert butyldimethylsilyl 10 hydroxyCamptothecin displays high lipophilicity improved human blood stability and potent anticancer activity
    Journal of Medicinal Chemistry, 2000
    Co-Authors: David Bom, Glenda Kohlhagen, Dennis P Curran, Stefan Kruszewski, Stephen G Zimmer, Thompson J Strode, Ashok J Chavan, Kimberly A Fraley, Alex L Bingcang, Lori J Latus
    Abstract:

    We describe the rational design and synthesis of B- and A,B-ring-modified Camptothecins. The key α-hydroxy-δ-lactone pharmacophore in 7-tert-butyldimethylsilyl-10-hydroxyCamptothecin (DB-67, 14) displays superior stability in human blood when compared with clinically relevant Camptothecin analogues. In human blood 14 displayed a t1/2 of 130 min and a percent lactone at equilibrium value of 30%. The tert-butyldimethylsilyl group renders the new agent 25-times more lipophilic than Camptothecin, and 14 is readily incorporated, as its active lactone form, into cellular and liposomal bilayers. In addition, the dual 7-alkylsilyl and 10-hydroxy substitution in 14 enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell lines derived from eight distinct tumor types indicate that 14 is of comparable potency to campt...

  • the novel silatecan 7 tert butyldimethylsilyl 10 hydroxyCamptothecin displays high lipophilicity improved human blood stability and potent anticancer activity
    Journal of Medicinal Chemistry, 2000
    Co-Authors: David Bom, Glenda Kohlhagen, Dennis P Curran, Stefan Kruszewski, Stephen G Zimmer, Thompson J Strode, Ashok J Chavan, Kimberly A Fraley, Alex L Bingcang, Lori J Latus
    Abstract:

    We describe the rational design and synthesis of B- and A, B-ring-modified Camptothecins. The key alpha-hydroxy-delta-lactone pharmacophore in 7-tert-butyldimethylsilyl-10-hydroxyCamptothecin (DB-67, 14) displays superior stability in human blood when compared with clinically relevant Camptothecin analogues. In human blood 14 displayed a t(1/2) of 130 min and a percent lactone at equilibrium value of 30%. The tert-butyldimethylsilyl group renders the new agent 25-times more lipophilic than Camptothecin, and 14 is readily incorporated, as its active lactone form, into cellular and liposomal bilayers. In addition, the dual 7-alkylsilyl and 10-hydroxy substitution in 14 enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell lines derived from eight distinct tumor types indicate that 14 is of comparable potency to Camptothecin and 10-hydroxyCamptothecin, as well as the FDA-approved Camptothecin analogues topotecan and CPT-11. In addition, cell-free cleavage assays reveal that 14 is highly active and forms more stable top1 cleavage complexes than Camptothecin or SN-38. The impressive blood stability and cytotoxicity profiles for 14 strongly suggest that it is an excellent candidate for additional in vivo pharmacological and efficacy studies.

Karen J Bowman - One of the best experts on this subject based on the ideXlab platform.

  • differential effects of the poly adp ribose polymerase parp inhibitor nu1025 on topoisomerase i and ii inhibitor cytotoxicity in l1210 cells in vitro
    British Journal of Cancer, 2001
    Co-Authors: Karen J Bowman, David R Newell, A H Calvert, Nicola J Curtin
    Abstract:

    The potent novel poly(ADP-ribose) polymerase (PARP) inhibitor, NU1025, enhances the cytotoxicity of DNA-methylating agents and ionizing radiation by inhibiting DNA repair. We report here an investigation of the role of PARP in the cellular responses to inhibitors of topoisomerase I and II using NU1025. The cytotoxicity of the topoisomerase I inhibitor, Camptothecin, was increased 2.6-fold in L1210 cells by co-incubation with NU1025. Camptothecin-induced DNA strand breaks were also increased 2.5-fold by NU1025 and exposure to Camptothecin-activated PARP. In contrast, NU1025 did not increase the DNA strand breakage or cytotoxicity caused by the topoisomerase II inhibitor etoposide. Exposure to etoposide did not activate PARP even at concentrations that caused significant levels of apoptosis. Taken together, these data suggest that potentiation of Camptothecin cytotoxicity by NU1025 is a direct result of increased DNA strand breakage, and that activation of PARP by Camptothecin-induced DNA damage contributes to its repair and consequently cell survival. However, in L1210 cells at least, it would appear that PARP is not involved in the cellular response to etoposide-mediated DNA damage. On the basis of these data, PARP inhibitors may be potentially useful in combination with topoisomerase I inhibitor anticancer chemotherapy. © 2001 Cancer Research Campaign http://www.bjcancer.com