Papers by bertrand jean-claude
International Journal of Molecular Sciences, Sep 3, 2021
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European Journal of Cancer, Oct 1, 2022
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The introduction of Xeloda® (capecitabine) in the clinical management of breast cancer has signif... more The introduction of Xeloda® (capecitabine) in the clinical management of breast cancer has significantly improved survival in patients with mammary carcinoma. It is administered orally and first is metabolized in the liver by carboxylesterases to generate 5'-deoxy- 5-flurocytidine ribose (5'-DFCR), which is subsequently converted to 5'-deoxy-5-fluorouridine ribose (5'-DFUR) by cytidine deaminase. While the latter conversion takes place in tumour and normal tissues, the conversion of 5'-DFUR to the cytotoxic compound 5-FU, occurs principally in the tumour. This reaction is catalyzed by thymidine phosphorylase (TP), which is overexpressed in cancer cells. It has been observed that tumours expressing high levels of TP are the most responsive to capecitabine treatment. Therefore, it was hypothesized that conditions leading to an increase of TP expression could potentiate the action of capecitabine. Our recent studies in a panel of human breast cancer cell lines showed an increase in TP levels upon exposure to gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR). Here, we report on the factors influencing the potency of gefitinib in combination with 5'-DFUR, the bioactive metabolite of capecitabine. The results showed that: 1) 5'-DFUR activity linearly correlated with TP basal level (R2= 0.808), 2) importantly, the strength of the synergistic interaction between gefitinib and 5'-DFUR, as measured by the combination index at IC50 concentrations (CI50) increased with TP fold changes after gefitinib treatment (R2=0.6449), 3) inversely, it decreased with increasing thymidylate synthase (TS) fold changes after gefitinib treatment (R2=0.6229), 4) moreover, the strength of the synergy correlated with an increase in the proportion of cells arrested in the S and G2M phases of cell cycle (R2=0.6355), 5) changes in TP levels correlated with the magnitude of inhibition of EGFR phosphorylation by gefitinib (R2=0.63) but not with its IC50 values for growth inhibition in the cell panel (R2=0.03611), 6) likewise, DNA damage induced by 5'-DFUR alone or in combination with gefitinib did not correlate with IC50 values for growth inhibition. The results in toto suggest that the observed synergistic interactions between gefitinib and 5'-DFUR may be imputed to molecular events associated with inhibition EGFR phosphorylation and modulation of TP/TS expression in the cells. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A44.
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Table S3 summarizes the complete blood count (CBC) and biochemistry assessment of alanine aminotr... more Table S3 summarizes the complete blood count (CBC) and biochemistry assessment of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes for ZR2002 alternate treatment (schedule #1).
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Table S1 summarizes molecular and genomic characteristics of GBM cell lines and GSCs.
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Purpose:Glioblastoma (GBM) is a fatal primary malignant brain tumor. GBM stem cells (GSC) contrib... more Purpose:Glioblastoma (GBM) is a fatal primary malignant brain tumor. GBM stem cells (GSC) contribute to resistance to the DNA-damaging chemotherapy, temozolomide. The epidermal growth factor receptor (EGFR) displays genomic alterations enabling DNA repair mechanisms in half of GBMs. We aimed to investigate EGFR/DNA combi-targeting in GBM.Experimental Design:ZR2002 is a “combi-molecule” designed to inflict DNA damage through its chlorethyl moiety and induce irreversible EGFR tyrosine kinase inhibition. We assessed its in vitro efficacy in temozolomide-resistant patient-derived GSCs, mesenchymal temozolomide-sensitive and resistant in vivo–derived GSC sublines, and U87/EGFR isogenic cell lines stably expressing EGFR/wild-type or variant III (EGFRvIII). We evaluated its antitumor activity in mice harboring orthotopic EGFRvIII or mesenchymal TMZ-resistant GSC tumors.Results:ZR2002 induced submicromolar antiproliferative effects and inhibited neurosphere formation of all GSCs with margin...
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Figure S3 shows ZR2002 alternate (schedule#1) or continuous (schedule#2) treatment protocol (A) a... more Figure S3 shows ZR2002 alternate (schedule#1) or continuous (schedule#2) treatment protocol (A) and monitoring mice body weights for alternate (B) or continuous (C) treatment.
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Figure S4 shows body weights assessment for mice with orthotopic U87/EGFRvIII (A) or TMZ-resistan... more Figure S4 shows body weights assessment for mice with orthotopic U87/EGFRvIII (A) or TMZ-resistant GSC (1123IC7R) tumors (B) treated with vehicle control or ZR2002 using alternate (A) or continuous treatment (B).
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Supplementary Legend
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International Journal of Molecular Sciences, 2021
The median-effect principle proposed by Chou and Talalay is the most effective approach to parame... more The median-effect principle proposed by Chou and Talalay is the most effective approach to parameterize interactions between several agents in combination. However, this method cannot be used to evaluate the effectiveness of equimolar drug combinations, which are comparative references for dual-targeting molecular design. Here, using data acquired through the development of “combi-molecules” blocking two kinases (e.g., EGFR-c-Src and EGFR-c-Met), we established potency indices for equimolar and dual-targeted inhibitors. If the fold difference (κ) between the IC50 of the two individual kinase inhibitors was >6, the IC50 of their equimolar combination resembled that of the more potent inhibitor. Hence, the “combi-targeting” of the two kinases was considered “imbalanced” and the combination ineffective. However, if κ ≤ 6, the IC50 of the combination fell below that of each individual drug and the combi-targeting was considered “balanced” and the combination effective. We also showed...
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Oncotarget, Jan 12, 2018
Disordered expression of the epidermal growth factor receptor (EGFR) has been associated with ind... more Disordered expression of the epidermal growth factor receptor (EGFR) has been associated with induction of DNA repair genes (e.g. XRCC1, ERCC1) and resistance to radiation and genotoxic drugs. However, our previous work showed that EGFR inhibition did not affect O-methylguanine-DNA methyltransferase (MGMT)-mediated resistance. In order to block uncoupled events associated with EGFR and MGMT, we designed MR30, a single molecule termed "combi-molecule" that contains a quinazoline arm targeted to EGFR and an O-benzylguanine (O-BG) moiety to block MGMT. Molecular analysis of the mechanism of action of its two arms showed that: (a) it could block EGFR phosphorylation, (b) down-regulate the RAF-MAPK and the PI3K-AKT pathways, and (c) covalently modify MGMT through S-benzylation, as confirmed by MALDI analysis of a direct binding assay with isolated MGMT, (d) it induced a dose-dependent down-regulation of MGMT in lung and melanoma cells. The pleiotropic mechanism of action of MR3...
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BMC cancer, Jan 11, 2017
Mutations of the DNA repair proteins BRCA1/2 are synthetically lethal with the DNA repair enzyme ... more Mutations of the DNA repair proteins BRCA1/2 are synthetically lethal with the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), which when inhibited, leads to cell death due to the absence of compensatory DNA repair mechanism. The potency of PARP inhibitors has now been clinically proven. However, disappointingly, acquired resistance mediated by the reactivation of wild type BRCA1/2 has been reported. In order to improve their efficacy, trials are ongoing to explore their combinations with temozolomide (TMZ). Here, in order to enhance potency in BRCA1/2-mutant cells, we report on the design of single molecules termed "combi-molecules" capable of not only inhibiting PARP but also damaging DNA like TMZ, which is known to induce a large number of DNA adducts. The majority of these lesions are processed through PARP-dependent base-excision repair machinery. Paradoxically, the least abundant lesion, the O6-methylguanine adduct is the most cytotoxic. Its repair by the O6-me...
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British Journal of Cancer, 1997
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OncoTargets and Therapy, 2015
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Journal of Molecular Structure: THEOCHEM, 2001
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International journal of radiation oncology, biology, physics, Jan 27, 2015
ZRBA1 is a combi-molecule designed to induce DNA alkylating lesions and to block epidermal growth... more ZRBA1 is a combi-molecule designed to induce DNA alkylating lesions and to block epidermal growth factor receptor (EGFR) TK domain. Inasmuch as ZRBA1 downregulates the EGFR TK-mediated antisurvival signaling and induces DNA damage, we postulated that it might be a radiosensitizer. The aim of this study was to further investigate the potentiating effect of ZRBA1 in combination with radiation and to elucidate the possible mechanisms of interaction between these 2 treatment modalities. The triple negative human breast MDA-MB-468 cancer cell line and mouse mammary cancer 4T1 cell line were used in this study. Clonogenic assay, Western blot analysis, and DNA damage analysis were performed at multiple time points after treatment. To confirm our in vitro findings, in vivo tumor growth delay assay was performed. Our results show that a combination of ZRBA1 and radiation increases the radiation sensitivity of both cell lines significantly with a dose enhancement factor of 1.56, induces signi...
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PLOS ONE, 2015
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Molecular Cancer Therapeutics, 2009
Capecitabine is a potent antitumor drug used in the treatment of many types of cancer such as bow... more Capecitabine is a potent antitumor drug used in the treatment of many types of cancer such as bowel, breast and stomach cancer. It is administered orally and is first metabolized in the liver by carboxylesterase to generate 5′-deoxy-5-flurocytidine ribose (5′-DFCR) that is subsequently converted to 5′-deoxy-5-fluorouridine ribose (5′-DFUR) by cytidine deaminase. While 5′-DFCR can be further converted to 5′-DFUR in tumor or normal tissues, the conversion of 5′-DFUR to the cytotoxic inhibitor of DNA synthesis 5-FU, is catalyzed by thymidine phosphorylase (TP), which is highly expressed in tumors. Factors modulating the TP levels in tumors are not well understood, however, recent reports suggest that drugs such as taxol and epidermal growth factor receptor (EGFR) inhibitors could induce an increase in TP levels in tumor cells. Here, we sought to determine whether inhibition of EGFR could modulate the levels of TP in a panel of six breast cancer cell lines with varied levels of sensitiv...
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Molecular Cancer Research, 2011
To enhance the potency of current EGFR inhibitors, we developed a novel strategy that seeks to co... more To enhance the potency of current EGFR inhibitors, we developed a novel strategy that seeks to confer them an additional DNA damaging function, leading to the design of drugs termed combi-molecules. ZRS1 is a novel combi-molecule that contains an EGFR tyrosine kinase targeting quinazoline arm and a methyltriazene-based DNA damaging one. We examined its effect on human tumor cell lines with varied levels of EGFR and O6-methylguanine DNA methyltransferase (MGMT). ZRS1 was more potent than the clinical methylating agent temozolomide in all cell lines, regardless of their MGMT status. However, its potency was in the same range as or less than that of Iressa, an EGFR inhibitor, against MGMT-proficient cells. In the MGMT-deficient or in MGMT-proficient cells exposed to the MGMT inhibitor O6-benzylguanine, its potency was superior to that of Iressa and temozolomide or a temozolomide+Iressa combination. Cell signaling analysis in A549 (MGMT+) and A427 (MGMT−) showed that ZRS1 strongly inhib...
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Leukemia, 2011
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Papers by bertrand jean-claude