Molecular Analysis of the Superior Efficacy of a Dual Epidermal Growth Factor Receptor (EGFR)-DNA-Targeting Combi-Molecule in Comparison with Its Putative Prodrugs 6-Mono-Alkylamino- and 6,6-Dialkylaminoquinazoline in a Human Osteosarcoma Xenograft Model
<i>Background</i>: ZR2002 is a dual EGFR-DNA-targeting combi-molecule that carries a chloroethyl group at the six-position of the quinazoline ring designed to alkylate DNA. Despite its good pharmacokinetics, ZR2002 is metabolized in vivo into dechlorinated metabolites, losing the DNA-alk...
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MDPI AG
2023-03-01
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| author | Caterina Facchin Ana B. Fraga-Timiraos Julie Schmitt Nadia Babaa Naveet Pannu Antonio Aliaga Anne-Laure Larroque Bertrand J. Jean-Claude |
| author_facet | Caterina Facchin Ana B. Fraga-Timiraos Julie Schmitt Nadia Babaa Naveet Pannu Antonio Aliaga Anne-Laure Larroque Bertrand J. Jean-Claude |
| author_sort | Caterina Facchin |
| collection | DOAJ |
| description | <i>Background</i>: ZR2002 is a dual EGFR-DNA-targeting combi-molecule that carries a chloroethyl group at the six-position of the quinazoline ring designed to alkylate DNA. Despite its good pharmacokinetics, ZR2002 is metabolized in vivo into dechlorinated metabolites, losing the DNA-alkylating function required to damage DNA. To increase the DNA damage activity in tumor cells in vivo, we compared ZR2002 with two of its 6-N,N-disubstituted analogs: “JS61”, with a nitrogen mustard function at the six-position of the quinazoline ring, and “JS84”, with an N-methyl group. <i>Methods</i>: Tumor xenografts were performed with the human Saos-2 osteosarcoma cell line expressing EGFR. Mice were treated with ZR2002, JS84 or JS61, and the tumor burden was measured with a caliper and CT/PET imaging. Drug metabolism was analyzed with LC-MS. EGFR and ɣ-H2AX phosphorylation were quantified via Western blot analysis and immunohistochemistry. <i>Results:</i> In vivo analysis showed that significant tumor growth inhibition was only achieved when ZR2002 was administered in its naked form. The metabolic dealkylation of JS61 and JS84 did not release sufficient concentrations of ZR2002 for the intratumoral inhibition of P-EGFR or enhanced levels of P-H2AX. <i>Conclusions</i>: The results in toto suggest that intratumoral concentrations of intact ZR2002 are correlated with the highest inhibition of P-EGFR and induction of DNA damage in vivo. ZR2002 may well represent a good drug candidate for the treatment of EGFR-expressing osteosarcoma. |
| first_indexed | 2024-03-11T06:47:56Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T06:47:56Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-bab38f54266047238e6fe55c77e6e1682023-11-17T10:13:39ZengMDPI AGCells2073-44092023-03-0112691410.3390/cells12060914Molecular Analysis of the Superior Efficacy of a Dual Epidermal Growth Factor Receptor (EGFR)-DNA-Targeting Combi-Molecule in Comparison with Its Putative Prodrugs 6-Mono-Alkylamino- and 6,6-Dialkylaminoquinazoline in a Human Osteosarcoma Xenograft ModelCaterina Facchin0Ana B. Fraga-Timiraos1Julie Schmitt2Nadia Babaa3Naveet Pannu4Antonio Aliaga5Anne-Laure Larroque6Bertrand J. Jean-Claude7Cancer Drug Research Laboratory, The Research Institute of the McGill University Health Center (RI-MUHC), Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A 3J1, CanadaCancer Drug Research Laboratory, The Research Institute of the McGill University Health Center (RI-MUHC), Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A 3J1, CanadaCancer Drug Research Laboratory, The Research Institute of the McGill University Health Center (RI-MUHC), Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A 3J1, CanadaCancer Drug Research Laboratory, The Research Institute of the McGill University Health Center (RI-MUHC), Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A 3J1, CanadaCancer Drug Research Laboratory, The Research Institute of the McGill University Health Center (RI-MUHC), Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A 3J1, CanadaCancer Drug Research Laboratory, The Research Institute of the McGill University Health Center (RI-MUHC), Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A 3J1, CanadaCancer Drug Research Laboratory, The Research Institute of the McGill University Health Center (RI-MUHC), Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A 3J1, CanadaCancer Drug Research Laboratory, The Research Institute of the McGill University Health Center (RI-MUHC), Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A 3J1, Canada<i>Background</i>: ZR2002 is a dual EGFR-DNA-targeting combi-molecule that carries a chloroethyl group at the six-position of the quinazoline ring designed to alkylate DNA. Despite its good pharmacokinetics, ZR2002 is metabolized in vivo into dechlorinated metabolites, losing the DNA-alkylating function required to damage DNA. To increase the DNA damage activity in tumor cells in vivo, we compared ZR2002 with two of its 6-N,N-disubstituted analogs: “JS61”, with a nitrogen mustard function at the six-position of the quinazoline ring, and “JS84”, with an N-methyl group. <i>Methods</i>: Tumor xenografts were performed with the human Saos-2 osteosarcoma cell line expressing EGFR. Mice were treated with ZR2002, JS84 or JS61, and the tumor burden was measured with a caliper and CT/PET imaging. Drug metabolism was analyzed with LC-MS. EGFR and ɣ-H2AX phosphorylation were quantified via Western blot analysis and immunohistochemistry. <i>Results:</i> In vivo analysis showed that significant tumor growth inhibition was only achieved when ZR2002 was administered in its naked form. The metabolic dealkylation of JS61 and JS84 did not release sufficient concentrations of ZR2002 for the intratumoral inhibition of P-EGFR or enhanced levels of P-H2AX. <i>Conclusions</i>: The results in toto suggest that intratumoral concentrations of intact ZR2002 are correlated with the highest inhibition of P-EGFR and induction of DNA damage in vivo. ZR2002 may well represent a good drug candidate for the treatment of EGFR-expressing osteosarcoma.https://www.mdpi.com/2073-4409/12/6/914combi-moleculeosteosarcomaDNA damageEGFR |
| spellingShingle | Caterina Facchin Ana B. Fraga-Timiraos Julie Schmitt Nadia Babaa Naveet Pannu Antonio Aliaga Anne-Laure Larroque Bertrand J. Jean-Claude Molecular Analysis of the Superior Efficacy of a Dual Epidermal Growth Factor Receptor (EGFR)-DNA-Targeting Combi-Molecule in Comparison with Its Putative Prodrugs 6-Mono-Alkylamino- and 6,6-Dialkylaminoquinazoline in a Human Osteosarcoma Xenograft Model Cells combi-molecule osteosarcoma DNA damage EGFR |
| title | Molecular Analysis of the Superior Efficacy of a Dual Epidermal Growth Factor Receptor (EGFR)-DNA-Targeting Combi-Molecule in Comparison with Its Putative Prodrugs 6-Mono-Alkylamino- and 6,6-Dialkylaminoquinazoline in a Human Osteosarcoma Xenograft Model |
| title_full | Molecular Analysis of the Superior Efficacy of a Dual Epidermal Growth Factor Receptor (EGFR)-DNA-Targeting Combi-Molecule in Comparison with Its Putative Prodrugs 6-Mono-Alkylamino- and 6,6-Dialkylaminoquinazoline in a Human Osteosarcoma Xenograft Model |
| title_fullStr | Molecular Analysis of the Superior Efficacy of a Dual Epidermal Growth Factor Receptor (EGFR)-DNA-Targeting Combi-Molecule in Comparison with Its Putative Prodrugs 6-Mono-Alkylamino- and 6,6-Dialkylaminoquinazoline in a Human Osteosarcoma Xenograft Model |
| title_full_unstemmed | Molecular Analysis of the Superior Efficacy of a Dual Epidermal Growth Factor Receptor (EGFR)-DNA-Targeting Combi-Molecule in Comparison with Its Putative Prodrugs 6-Mono-Alkylamino- and 6,6-Dialkylaminoquinazoline in a Human Osteosarcoma Xenograft Model |
| title_short | Molecular Analysis of the Superior Efficacy of a Dual Epidermal Growth Factor Receptor (EGFR)-DNA-Targeting Combi-Molecule in Comparison with Its Putative Prodrugs 6-Mono-Alkylamino- and 6,6-Dialkylaminoquinazoline in a Human Osteosarcoma Xenograft Model |
| title_sort | molecular analysis of the superior efficacy of a dual epidermal growth factor receptor egfr dna targeting combi molecule in comparison with its putative prodrugs 6 mono alkylamino and 6 6 dialkylaminoquinazoline in a human osteosarcoma xenograft model |
| topic | combi-molecule osteosarcoma DNA damage EGFR |
| url | https://www.mdpi.com/2073-4409/12/6/914 |
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