Histone H2AX phosphorylation as a molecular pharmacological marker for DNA interstrand crosslink cancer chemotherapy

Clingen, Peter H.; Wu, Jihong; Miller, Jodi; Mistry, N.; Chin, Frederick T.; Wynne, P; Prise, Kevin M.; Hartley, John A.

doi:10.1016/j.bcp.2008.03.025

Cited by 117 publications

(125 citation statements)

References 31 publications

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“…This faster ICL repair is consistent with the ␥H2AX data. ␥H2AX foci formation the molecular marker for DNA DSB repair in general and the repair of DNA interstrand cross-links induced by several anticancer agents (28,39). This effect was observed at 48 and 72 h but not at 24 h, which could likely be due to the requirement of cytosine deamination at the cisplatin ICL prior to an involvement of BER (Model 1).…”

Section: Discussionmentioning

confidence: 99%

Novel Role of Base Excision Repair in Mediating Cisplatin Cytotoxicity

Kothandapani

Dangeti

Brown

et al. 2011

Journal of Biological Chemistry

121

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Using isogenic mouse embryonic fibroblasts and human cancer cell lines, we show that cells defective in base excision repair (BER) display a cisplatin-specific resistant phenotype. This was accompanied by enhanced repair of cisplatin interstrand crosslinks (ICLs) and ICL-induced DNA double strand breaks, but not intrastrand adducts. Cisplatin induces abasic sites with a reduced accumulation in uracil DNA glycosylase (UNG) null cells. We show that cytosines that flank the cisplatin ICLs undergo preferential oxidative deamination in vitro, and AP endonuclease 1 (APE1) can cleave the resulting ICL DNA substrate following removal of the flanking uracil. We also show that DNA polymerase ␤ has low fidelity at the cisplatin ICL site after APE1 incision. Down-regulating ERCC1-XPF in BER-deficient cells restored cisplatin sensitivity. Based on our results, we propose a novel model in which BER plays a positive role in maintaining cisplatin cytotoxicity by competing with the productive cisplatin ICL DNA repair pathways.

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Section: Discussionmentioning

confidence: 99%

Novel Role of Base Excision Repair in Mediating Cisplatin Cytotoxicity

Kothandapani

Dangeti

Brown

et al. 2011

Journal of Biological Chemistry

121

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“…20 Previous studies have shown that gH2AX can act as a highly sensitive and general marker of DNA damage induced by various ICL-inducing agents such as nitrogen mustards and platinumbased drugs. [21][22][23] Repair of DNA and, thus, preservation of the genetic code are critical for normal cellular function. 24 However, tumor cells use DNA repair pathways to develop resistance to chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

DNA repair of myeloma plasma cells correlates with clinical outcome: the effect of the nonhomologous end-joining inhibitor SCR7

Γκοτζαμανίδου

Terpos

Bamia

et al. 2016

Blood

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Key Points• Responders to melphalan therapy are characterized by slower rates of NER and DSB/R mechanisms and higher apoptotic rates.• The DSB/R inhibitor SCR7 enhances cytotoxicity of melphalan against myeloma plasma cells.DNA repair activity of malignant cells seems to influence therapeutic outcome and patients' survival. Herein, we investigated the mechanistic basis for the link between DNA repair efficiency and response to antimyeloma therapy. Nucleotide excision repair (NER), interstrand cross-links repair (ICL/R), double-strand breaks repair (DSB/R), and chromatin structure were evaluated in multiple myeloma (MM) cell lines (melphalan-sensitive RPMI8226; melphalan-resistant LR5) and bone marrow plasma cells (BMPCs) from MM patients who responded (n 5 17) or did not respond (n 5 9) to subsequent melphalan therapy. The effect of DSB/R inhibition was also evaluated. Responders' BMPCs showed slower rates of NER and DSB/R (P < .0022), similar rates of ICL/R, and more condensed chromatin structure compared with nonresponders. Moreover, apoptosis rates of BMPCs were inversely correlated with individual DNA repair efficiency and were higher in responders' cells compared with those of nonresponders (P 5 .0011). Similarly, RPMI8226 cells showed slower rates of NER and DSB/R, comparable rates of ICL/R, more condensed chromatin structure, and higher sensitivity than LR5 cells. Interestingly, cotreatment of BMPCs or cell lines with DSB/R inhibitors significantly reduced the rates of DSB/R and increased melphalan sensitivity of the cells, with the nonhomologous end-joining inhibitor SCR7 showing the strongest effect. Together, responders' BMPCs are characterized by lower efficiencies of NER and DSB/R mechanisms, resulting in higher accumulation of the extremely cytotoxic ICLs and DSBs lesions, which in turn triggers the induction of the apoptotic pathway. Moreover, the enhancement of melphalan cytotoxicity by DSB/R inhibition offers a promising strategy toward improvement of existing antimyeloma regimens. (Blood. 2016;128(9):1214-1225

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“…In our study, increased phosphorylation of H2AX and higher interstrand crosslinks suggest superior alkylating properties of RXDX-107. The interstrand crosslinks and phosphorylation of H2AX are known DNA damage markers, induced by multiple chemo agents, including bendamustine [4,[16][17][18]. However, the degree of DNA damage is rate limiting, the moderate DNA damage can be repaired in many cancer cell lines, [19][20][21].…”

Section: Discussionmentioning

confidence: 99%

RXDX-107, A Dodecanol Alkyl Ester of Bendamustine, Demonstrates Greater Stability and Broad Antitumor Activity in Multiple Pre-Clinical Models of Solid Tumor

Martin¹,

Johnson²,

Patel³

et al. 2016

Chemotherapy

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Purpose: RXDX-107 is a dodecanol alkyl ester of bendamustine encapsulated in human serum albumin (HSA) to form nanoparticles. The anti-tumor activity of bendamustine in solid tumor malignancies has been less impressive, partially due to short half-life. RXDX-107 was designed to extend the half-life and improve tissue biodistribution over bendamustine, which may result in superior efficacy and tolerability in patients with solid tumors. Experimental Design:The anti-tumor activity of RXDX-107 was measured in cellular anti-proliferation assay, cell-line derived xenograft (CDX) models and patient-derived xenograft (PDX) models. The mechanism of action and pharmacodynamics properties were measured by comet assay. The tumor accumulation was measured by a novel LC-MS/MS method. Results:In in vitro anti-proliferative studies, RXDX-107 displayed dose-dependent cytotoxicity against multiple solid tumor cell lines. While the IC50 of RXDX-107 were comparable to those of bendamustine, RXDX-107 displayed more complete cell killing. RXDX-107 exhibited enhanced pharmacodynamics properties, including stronger induction of pH2AX (a biomarker for DNA damage) and higher interstrand crosslinks (ICLs) formation. RXDX-107 significantly reduces tumor growth in human NSCLC xenograft models. RXDX-107 also showed single agent anti-tumor activities, including tumor regression in multiple PDX models of solid tumors including breast, lung, and ovarian cancer. Furthermore, the mode of action data exhibit slow and sustained release of bendamustine from RXDX-107, and high intratumoral accumulation of RXDX-107. Conclusions:Our preclinical data demonstrate potent and broad anti-tumor activity of RXDX-107 across a variety of solid tumor types, and support further clinical development of this novel drug candidate for the treatment of solid tumors.

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Histone H2AX phosphorylation as a molecular pharmacological marker for DNA interstrand crosslink cancer chemotherapy

Cited by 117 publications

References 31 publications

Novel Role of Base Excision Repair in Mediating Cisplatin Cytotoxicity

Novel Role of Base Excision Repair in Mediating Cisplatin Cytotoxicity

DNA repair of myeloma plasma cells correlates with clinical outcome: the effect of the nonhomologous end-joining inhibitor SCR7

RXDX-107, A Dodecanol Alkyl Ester of Bendamustine, Demonstrates Greater Stability and Broad Antitumor Activity in Multiple Pre-Clinical Models of Solid Tumor

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