p53 Elevation in Relation to Levels and Cytotoxicity of Mono- and Bifunctional Melphalan-DNA Adducts

Gould, Katherine A.; Nixon, Cally; Tilby, Michael J.

doi:10.1124/mol.104.000596

Cited by 22 publications

(19 citation statements)

References 28 publications

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“…However, it did not have any effect on the sensitivity of cells to ionising radiation or temozolomide. NU2058 also potentiated the monofunctional derivative of melphalan, monohydroxymelphalan; however, as expected from previous studies with ML-1 cells [25] monohydroxymelphalan was approximately 20-fold less toxic than melphalan towards SQ20b cells (Fig. 4F)…”

Section: Discussionsupporting

confidence: 84%

The kinase inhibitor O6-cyclohexylmethylguanine (NU2058) potentiates the cytotoxicity of cisplatin by mechanisms that are independent of its effect upon CDK2

Harrison¹,

Ottley²,

Pearson³

et al. 2009

Biochemical Pharmacology

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O(6)-Cyclohexylmethylguanine (NU2058) was developed as an inhibitor of CDK2 and was previously shown to potentiate cisplatin cytotoxicity in vitro. The aim of this study was to investigate the mechanism of cisplatin potentiation by NU2058. SQ20b, head and neck cancer cells were treated for 2h with NU2058 (100 microM) and then for a further 2h with cisplatin and NU2058. NU2058 increased cisplatin cytotoxicity, by clonogenic assay, with a dose modification factor (DMF) of 3.1. NU2058 increased total intracellular platinum levels 1.5-fold, and platinum-DNA adduct levels twofold. Furthermore, the cisplatin-DNA adducts formed were more toxic in the presence of NU2058. To investigate whether the effects of NU2058 on cisplatin adduct levels and toxicity were dependent on CDK2 activity, additional CDK2 inhibitors were tested. NU6230 (CDK2 IC(50) 18 microM) was equipotent to NU2058 (CDK2 IC(50) 17 microM) as a CDK2 inhibitor in cell-free and cell-based assays, yet did not potentiate cisplatin cytotoxicity. Furthermore, NU6102 was >1000-fold more potent than NU2058 as a CDK2 inhibitor (CDK2 IC(50) 5 nM) yet was no more active than NU2058 in potentiating cisplatin. NU2058 also potentiated melphalan (DMF 2.3), and monohydroxymelphalan (1.7), but not temozolomide or ionising radiation. Whilst NU2058 increased melphalan cytotoxicity, it did not increase melphalan-DNA adduct formation. These studies demonstrate that NU2058 alters the transport of cisplatin, causing more Pt-DNA adducts, as well as sensitizing cells to cisplatin- and melphalan-induced DNA damage. However, the effects of NU2058 are independent of CDK2 inhibition.

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Section: Discussionsupporting

confidence: 84%

The kinase inhibitor O6-cyclohexylmethylguanine (NU2058) potentiates the cytotoxicity of cisplatin by mechanisms that are independent of its effect upon CDK2

Harrison¹,

Ottley²,

Pearson³

et al. 2009

Biochemical Pharmacology

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“…Melphalan is a nitrogen mustard chemotherapeutic that induces DNA ICLs in the major groove of DNA and is used clinically in the treatment of several cancers including multiple myeloma (23). The mono-functional analogues mono-melphalan (24,25) and mmy-SJG are capable of producing mono-adducts in the major and minor groove, respectively but not DNA ICLs. These agents were included in this investigation in order to understand the importance of ICLs with respect to cytotoxicity of both melphalan and SJG-136.…”

Section: Introductionmentioning

confidence: 99%

The XPF-ERCC1 endonuclease and homologous recombination contribute to the repair of minor groove DNA interstrand crosslinks in mammalian cells produced by the pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136

Clingen

Silva²,

McHugh

et al. 2005

Nucleic Acids Research

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SJG-136, a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer, is a highly efficient interstrand crosslinking agent that reacts with guanine bases in a 5′-GATC-3′ sequence in the DNA minor groove. SJG-136 crosslinks form rapidly and persist compared to those produced by conventional crosslinking agents such as nitrogen mustard, melphalan or cisplatin which bind in the DNA major groove. A panel of Chinese hamster ovary (CHO) cells with defined defects in specific DNA repair pathways were exposed to the bi-functional agents SJG-136 and melphalan, and to their mono-functional analogues mmy-SJG and mono-functional melphalan. SJG-136 was >100 times more cytotoxic than melphalan, and the bi-functional agents were much more cytotoxic than their respective mono-functional analogues. Cellular sensitivity of both SJG-136 and melphalan was dependent on the XPF-ERCC1 heterodimer, and homologous recombination repair factors XRCC2 and XRCC3. The relative level of sensitivity of these repair mutant cell lines to SJG-136 was, however, significantly less than with major groove crosslinking agents. In contrast to melphalan, there was no clear correlation between sensitivity to SJG-136 and crosslink unhooking capacity measured using a modified comet assay. Furthermore, repair of SJG-136 crosslinks did not involve the formation of DNA double-strand breaks. SJG-136 cytotoxicity is likely to result from the poor recognition of DNA damage by repair proteins resulting in the slow repair of both mono-adducts and more importantly crosslinks in the minor groove.

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“…The cytotoxic actions of melphalan derive from the formation of DNA adducts and subsequent initiation of apoptosis and cell death (37,38). The increased formation of DNA adducts in the melphalan plus ADH-1-treated xenografts suggests that the increased apoptosis observed in these xenografts was at least in part a consequence of enhanced adduct formation.…”

Section: Discussionmentioning

confidence: 99%

Targeting N-Cadherin Enhances Antitumor Activity of Cytotoxic Therapies in Melanoma Treatment

et al. 2008

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Malignant transformation in melanoma is characterized by a phenotype ''switch'' from E-to N-cadherin, which is associated with increased motility and invasiveness of the tumor and altered signaling, leading to decreased apoptosis. We hypothesized that the novel pentapeptide (ADH-1), which disrupts N-cadherin adhesion, could sensitize melanoma tumors to the cytotoxic effects of chemotherapy. N-cadherinexpressing human melanoma-derived cell lines were used to generate xenografts in animal models to study isolated limb infusion with melphalan and systemic chemotherapy with temozolomide. We report here that melphalan in combination with ADH-1 significantly reduced tumor growth up to 30-fold over melphalan alone. ADH-1 enhancement of response to melphalan was associated with increased formation of DNA adducts, increased apoptosis, and intracellular signaling changes associated with focal adhesions and fibroblast growth factor receptors. Targeted therapy using an N-cadherin antagonist can dramatically augment the antitumor effects of chemotherapy and is a novel approach to optimizing treatment for melanoma. [Cancer Res 2008;68(10):3777-84]

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p53 Elevation in Relation to Levels and Cytotoxicity of Mono- and Bifunctional Melphalan-DNA Adducts

Cited by 22 publications

References 28 publications

The kinase inhibitor O6-cyclohexylmethylguanine (NU2058) potentiates the cytotoxicity of cisplatin by mechanisms that are independent of its effect upon CDK2

The kinase inhibitor O6-cyclohexylmethylguanine (NU2058) potentiates the cytotoxicity of cisplatin by mechanisms that are independent of its effect upon CDK2

The XPF-ERCC1 endonuclease and homologous recombination contribute to the repair of minor groove DNA interstrand crosslinks in mammalian cells produced by the pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136

Targeting N-Cadherin Enhances Antitumor Activity of Cytotoxic Therapies in Melanoma Treatment

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