Combined treatment with temozolomide and poly(ADP-ribose) polymerase inhibitor enhances survival of mice bearing hematologic malignancy at the central nervous system site

Tentori, Lucio; Leonetti, Carlo; Scarsella, Marco; d’Amati, Giulia; Portarena, Ilaria; Zupi, Gabriella; Bonmassar, Enzo; Graziani, Grazia

doi:10.1182/blood.v99.6.2241

Cited by 76 publications

(45 citation statements)

References 17 publications

(17 reference statements)

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“…Elevated PARP expression has also been shown to be associated with chemoresistance (21). These data further indicate that cancer cells may acquire enhanced PARP activity and pharmacologic inhibition of PARP has been shown to sensitize cancer cells to cancer therapeutics both in vitro and in animal models (24)(25)(26)(27)(28)(29)(30)(31)(32).…”

Section: Introductionmentioning

confidence: 89%

Potentiation of Temozolomide Cytotoxicity by Poly(ADP)Ribose Polymerase Inhibitor ABT-888 Requires a Conversion of Single-Stranded DNA Damages to Double-Stranded DNA Breaks

Liu¹,

Shi²,

Guan³

et al. 2008

Molecular Cancer Research

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Poly(ADP-ribose) polymerase (PARP) senses DNA breaks and facilitates DNA repair via the polyADP-ribosylation of various DNA binding and repair proteins. We explored the mechanism of potentiation of temozolomide cytotoxicity by the PARP inhibitor ABT-888. We showed that cells treated with temozolomide need to be exposed to ABT-888 for at least 17 to 24 hours to achieve maximal cytotoxicity. The extent of cytotoxicity correlates with the level of double-stranded DNA breaks as indicated by ;H2AX levels. In synchronized cells, damaging DNA with temozolomide in the presence of ABT-888 during the S phase generated high levels of double-stranded breaks, presumably because the single-stranded DNA breaks resulting from the cleavage of the methylated nucleotides were converted into double-stranded breaks through DNA replication. As a result, treatment of temozolomide and ABT-888 during the S phase leads to higher levels of cytotoxicity. ABT-888 inhibits poly(ADP-ribose) formation in vivo and enhances tumor growth inhibition by temozolomide in multiple models. ABT-888 is well tolerated in animal models. ABT-888 is currently in clinical trials in combination with temozolomide. (Mol Cancer Res 2008;6(10):1621 -9)

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Section: Introductionmentioning

confidence: 89%

Potentiation of Temozolomide Cytotoxicity by Poly(ADP)Ribose Polymerase Inhibitor ABT-888 Requires a Conversion of Single-Stranded DNA Damages to Double-Stranded DNA Breaks

Liu¹,

Shi²,

Guan³

et al. 2008

Molecular Cancer Research

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“…As described above, PARP inhibition results in cellular sensitization to the chemotherapeutic methylating agent TMZ, particularly in MMR-deficient cells, just as it does to the model methylating agents MMS and MNU [66,90,[93][94][95][96]. Further, preclinical studies have demonstrated that novel PARP inhibitors can enhance the antitumor activity of TMZ against mouse tumors and human colon and glioma xenograft models [72,[97][98][99]. TMZ is effective in the treatment of astrocytoma and glioblastoma since it is able to cross the blood-brain barrier [100,101], and combination regimens have been developed.…”

Section: Potential Role Of Ber Modulators In Chemotherapymentioning

confidence: 99%

Hypersensitivity phenotypes associated with genetic and synthetic inhibitor-induced base excision repair deficiency

Horton¹,

Wilson²

2007

DNA Repair

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Single-base lesions in DNA are repaired predominantly by base excision repair (BER). DNA polymerase β (pol β) is the polymerase of choice in the preferred single-nucleotide BER pathway. The characteristic phenotype of mouse fibroblasts with a deletion of the pol β gene is moderate hypersensitivity to monofunctional alkylating agents, e.g., methyl methanesulfonate (MMS). Increased sensitivity to MMS is also seen in the absence of pol β partner proteins XRCC1 and PARP-1, and under conditions where BER efficiency is reduced by synthetic inhibitors. PARP activity plays a major role in protection against MMS-induced cytotoxicity, and cells treated with a combination of non-toxic concentrations of MMS and a PARP inhibitor undergo cell cycle arrest and die by a Chk1-dependent apoptotic pathway. Since BER-deficient cells and tumors are similarly hypersensitive to the clinically used chemotherapeutic methylating agent temozolomide, modulation of DNA damage-induced cell signaling pathways, as well as BER, are attractive targets for potentiating chemotherapy.

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“…An additional treatment with the PARP inhibitor CEP-6800 potentiated the tumour growth reduction seen with the cytotoxic agents and, depending on the cell line used, even led to total regression of the tumours. 21 Tentori et al 22 injected lymphoma cells intracranially into mice and treated them systemically with TZM by single or repeated intraperitoneal administration. Double treatment with a PARP inhibitor at the same time as TZM by intracerebral injection of NU1025 significantly enhanced the survival of the tumour-bearing mice, with the fractionated TZM administration being most effective.…”

Section: Cancer Therapymentioning

confidence: 99%

Poly(ADP‐ribosyl)ation inhibitors: Promising drug candidates for a wide variety of pathophysiologic conditions

Beneke

Diefenbach

Bürkle

2004

Intl Journal of Cancer

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Poly(ADP-ribose) polymerases are involved in many aspects of regulation of cellular functions. Using NAD ؉ as a substrate, they catalyse the covalent transfer of ADP-ribose units onto several acceptor proteins to form a branched ADP-ribose polymer. The best characterised and first discovered member of this multiprotein family is PARP-1. Its catalytic activity is markedly stimulated upon binding to DNA strand interruptions, and the resulting polymer is thought to function in chromatin relaxation as well as in signalling the presence of damage to DNA repair complexes and in regulating enzyme activities. Moderate activation of PARP-1 facilitates the efficient repair of DNA damage arising from monofunctional alkylating agents, reactive oxygen species or ionising radiation, but severe genotoxic stress leads to rapid energy consumption and subsequently to necrotic cell death. The latter aspect of PARP-1 activity has been implicated in the pathogenesis of various clinical conditions such as shock, ischaemia-reperfusion and diabetes. Inhibition of ADP-ribose polymer formation has been shown to be effective, on the one hand, in the treatment of cancer in combination with alkylating agents by suppressing DNA repair and thus driving tumour cells into apoptosis, and on the other hand it appears to be a promising drug target for the treatment of pathologic conditions involving oxidative stress. In view of the existence of several members of the PARP family in mammalian cells, one has to be aware of possible side effects but also of a wide spectrum of potential clinical applications, which calls for the development of more specific inhibitors. © 2004 Wiley-Liss, Inc. Key words: DNA damage; PARP; cancer chemotherapy; radiotherapy; ischaemia-reperfusion damage; diabetes; shock; Parkinson syndromePoly(ADP-ribosyl)ation is a posttranslational modification of proteins in eukaryotic cells performed by a family of NAD ϩ ADP-ribosyl transferases, the poly(ADP-ribose) polymerases (PARPs). NAD ϩ molecules as precursor are cleaved into nicotinamide and ADP-ribose moieties, and the latter are covalently attached to glutamic or aspartic acid residues of proteins, with PARP itself being the major acceptor. Poly(ADP-ribosyl)ation may alter the activity of acceptor protein, leading to inactivation due to the attachment of a highly complex, branched polymer carrying large numbers of negative charges (Fig. 1). The polymer is rapidly degraded by the enzyme poly(ADP-ribose) glycohydrolase (PARG), limiting the half-life of the polymer to approximately 1 min under conditions of DNA breakage. Poly(ADPribosyl)ation was originally discovered as an immediate response of cells to DNA strand-break-inducing agents, i.e., ionising radiation, alkylating agents and oxidants. Polymer formation in living cells after genotoxic stresses is mainly dependent on PARP-1 (encoded by the ADPRT gene), the first-discovered and best-investigated member of the PARP family. After binding of PARP-1 with its 2 zinc-fingers within the N-terminal DNA-binding domain to double...

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Combined treatment with temozolomide and poly(ADP-ribose) polymerase inhibitor enhances survival of mice bearing hematologic malignancy at the central nervous system site

Cited by 76 publications

References 17 publications

Potentiation of Temozolomide Cytotoxicity by Poly(ADP)Ribose Polymerase Inhibitor ABT-888 Requires a Conversion of Single-Stranded DNA Damages to Double-Stranded DNA Breaks

Potentiation of Temozolomide Cytotoxicity by Poly(ADP)Ribose Polymerase Inhibitor ABT-888 Requires a Conversion of Single-Stranded DNA Damages to Double-Stranded DNA Breaks

Hypersensitivity phenotypes associated with genetic and synthetic inhibitor-induced base excision repair deficiency

Poly(ADP‐ribosyl)ation inhibitors: Promising drug candidates for a wide variety of pathophysiologic conditions

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