DNA interstrand cross-linking and TP53 status as determinants of tumour cell sensitivity in vitro to the antibody-directed enzyme prodrug therapy ZD2767

Monks, Noel R.; Blakey, David C.; East, Simon J.; Dowell, Robert I.; Calvete, J. A.; Curtin, Nicola J.; Arris, C.E; Newell, David R.

doi:10.1016/s0959-8049(02)00111-9

Cited by 22 publications

(17 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The observation that melphalan was approximately 23-fold more cytotoxic than monohydroxymelphalan is consistent with data for other alkylating agents in vivo (Ross, 1962) and in cell lines (Tokuda and Bodell, 1987;Monks et al, 2002;Palom et al, 2002). DNA adducts induced by melphalan were actually approximately 45 times more cytotoxic than the adducts induced by monohydroxymelphalan.…”

Section: Discussionsupporting

confidence: 88%

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

Gould

Nixon²,

Tilby³

2004

Mol Pharmacol

View full text Add to dashboard Cite

We tested the hypothesis that bifunctional DNA adducts formed by a nitrogen mustard-based anticancer drug were more efficient than monofunctional adducts at causing elevation of p53, consistent with the difference in cytotoxicity. Human leukemia cell line ML-1 was exposed for 1 h to melphalan or its monofunctional derivative monohydroxymelphalan. Levels of DNA adducts, measured by specific immunoassay, were linearly related to the concentration of alkylating agent. Monohydroxymelphalan formed twice as many adducts as did equal concentrations of melphalan. After the removal of the alkylating agent, adduct levels were maintained or increased slightly up to 8 h and then decreased by 27 to 44% by 24 h. Alkaline elution analyses confirmed the absence of detectable DNA interstrand cross-links in cells exposed to monohydroxymelphalan. DNA single-strand breaks were detected after monohydroxymelphalan but not after melphalan. Levels of p53 were quantified by sensitive fluorogenic enzyme-linked immunosorbent assay at intervals up to 24 h after exposure of cells to various concentrations of melphalan and monohydroxymelphalan. The level of initially formed DNA adducts needed to cause elevation of p53 from a baseline level of 0.5 ng/mg total protein to 2 ng/mg was 5-to 8-fold higher for monohydroxymelphalan than melphalan. The concentrations of melphalan and monohydroxymelphalan (ϮS.D.) causing 50% growth inhibition were 1.2 Ϯ 0.4 and 28.1 Ϯ 1.6 g/ml, respectively, a 23-fold difference. The adduct levels induced by these exposures were 9.3 and 420 nmol/g DNA for melphalan and monohydroxymelphalan, respectively, a 45-fold difference, which is considerably greater than the difference in efficacy at elevating p53.

show abstract

Section: Discussionsupporting

confidence: 88%

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

Gould

Nixon²,

Tilby³

2004

Mol Pharmacol

View full text Add to dashboard Cite

show abstract

“…3B). The quantitative relationship between cytotoxicity and cross-link formation has yet to be established, but the latter is a potential response biomarker with utility during clinical development of nitrogen mustard prodrugs (39). Of note, Ser 139 phosphorylation of histone H2AX to form gH2AX, a well-established biomarker of doublestrand break formation (40), was shown with both PR-104A and chlorambucil, with a greater response to PR-104 but not chlorambucil under hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Action and Preclinical Antitumor Activity of the Novel Hypoxia-Activated DNA Cross-Linking Agent PR-104

Patterson

Ferry

Edmunds

et al. 2007

Clinical Cancer Research

213

235

View full text Add to dashboard Cite

Purpose: Hypoxia is a characteristic of solid tumors and a potentially important therapeutic target. Here, we characterize the mechanism of action and preclinical antitumor activity of a novel hypoxia-activated prodrug, the 3,5-dinitrobenzamide nitrogen mustard PR-104, which has recently entered clinical trials. Experimental Design: Cytotoxicity in vitro was evaluated using 10 human tumor cell lines. SiHa cells were used to characterize metabolism under hypoxia, by liquid chromatography-mass spectrometry, and DNA damage by comet assay and gH2AX formation. Antitumor activity was evaluated in multiple xenograft models (PR-104 F radiation or chemotherapy) by clonogenic assay 18 h after treatment or by tumor growth delay. Results: The phosphate ester ''pre-prodrug'' PR-104 was well tolerated in mice and converted rapidly to the corresponding prodrug PR-104A. The cytotoxicity of PR-104A was increased 10-to 100-fold by hypoxia in vitro. Reduction to the major intracellular metabolite, hydroxylamine PR-104H, resulted in DNA cross-linking selectively under hypoxia. Reaction of PR-104H with chloride ion gave lipophilic cytotoxic metabolites potentially able to provide bystander effects. In tumor excision assays, PR-104 provided greater killing of hypoxic (radioresistant) and aerobic cells in xenografts (HT29, SiHa, and H460) than tirapazamine or conventional mustards at equivalent host toxicity. PR-104 showed single-agent activity in six of eight xenograft models and greater than additive antitumor activity in combination with drugs likely to spare hypoxic cells (gemcitabine with Panc-01pancreatic tumors and docetaxel with 22RV1prostate tumors). Conclusions: PR-104 is a novel hypoxia-activated DNA cross-linking agent with marked activity against human tumor xenografts, both as monotherapy and combined with radiotherapy and chemotherapy.Hypoxia is a uniquely attractive target in oncology for two reasons. The first is that hypoxic cells are obstacles to curative cancer therapy with all major treatment modalities. Hypoxia can compromise outcomes of surgery by increasing tumor metastasis (1 -3). It is also a major cause of radioresistance because oxygen is a radiosensitizer, and multiple clinical studies have documented the importance of hypoxia determining local tumor control in radiotherapy (4 -6). Hypoxia also contributes to chemoresistance through multiple mechanisms (7), including limitations on delivery of blood-borne drugs to hypoxic regions of tumors (8,9). The second reason for targeting hypoxia is that it is a common feature of a wide variety of human tumors and is typically more severe in tumors than in normal tissues, thus providing a basis for tumor selectivity (10,11).Several strategies for exploiting tumor hypoxia are now in preclinical or clinical development (7), with the main focus on prodrugs that are activated by metabolic reduction under hypoxic conditions to form cytotoxins. Early efforts focused on quinone bioreductive drugs, such as porfiromycin (12), and 2-nitroimidazole -linked alkylating a...

show abstract

“…32) and an activating enzyme carboxypeptidase G2 (CPG2) [55]. ZD2767D 96 is an alkylating agent derived from phenol and aniline mustards and currently under phase I clinical trial as a potential treatment for colorectal cancer [56].…”

Section: Antibody-directed Enzyme Prodrug Therapymentioning

confidence: 99%

DNA Interstrand Cross-Linking Agents and their Chemotherapeutic Potential

Brulíková

Hlaváč²,

Hradil

2012

CMC

View full text Add to dashboard Cite

DNA interstrand cross-linking (ICL) agents are an important group of cytotoxic drugs with the capability of binding covalently between two strands of DNA, thereby preventing vital processes such as replication or transcription in dividing cells. In anticancer therapy however, their potential is limited due to the resistance by various mechanisms. In order to develop highly effective antitumor drugs it is necessary to study both effective ICL formations and their subsequent repair mechanisms. This review presents an overview of development over the past decade and the use of both well-known and new DNA interstrand cross-linking agents. Their potential in applications especially as anticancer chemotherapeutics in the framework of current knowledge of repair mechanisms and development of combined chemotherapy is discussed.

show abstract

DNA interstrand cross-linking and TP53 status as determinants of tumour cell sensitivity in vitro to the antibody-directed enzyme prodrug therapy ZD2767

Cited by 22 publications

References 21 publications

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

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

Mechanism of Action and Preclinical Antitumor Activity of the Novel Hypoxia-Activated DNA Cross-Linking Agent PR-104

DNA Interstrand Cross-Linking Agents and their Chemotherapeutic Potential

Contact Info

Product

Resources

About