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F84, a quinazoline derivative, exhibits high potent antitumor activity against human gynecologic malignancies

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Summary

EGFR overexpression in gynecologic cancer has been associated with poor prognosis. Targeted inhibition of EGFR via its tyrosine kinase domain is a successful treatment in lung cancer. However, the results of existing clinical trials in gynecologic cancers do not show a significant clinical response to EGFR inhibition alone in unscreened patients. Novel EGFR-TKI might be beneficial for patients with gynecologic cancers. In this article, the in vitro and in vivo effects of a newly synthesized novel EGFR tyrosine kinase inhibitor N-(3-bromophenyl)-N-(7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-yl)-3,3-dimethylbutanamide (F84) is being reported. In vitro, F84 and PD153035 significantly inhibited the growth of four different human gynecologic cancer cell lines in a dose-dependent manner. In vivo, F84 exhibited an inhibitory effect on gynecologic malignancies. While the mechanism of action is still unclear, it might be related to inhibition of EGFR signaling pathway, delay in cell cycle progression and a G1 arrest together with a partial G2/M block and induction of apoptosis. These results suggest that F84 could be a potential drug candidate for the treatment of human gynecologic malignancies.

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References

  1. Jemal A (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43

    Article  PubMed  Google Scholar 

  2. McGuire WP (1996) Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and IV ovarian cancer. N Engl J Med 334:1–6. doi:10.1056/NEJM199601043340101

    Article  CAS  PubMed  Google Scholar 

  3. Ashouri S, Garcia AA (2007) Current status of signal transduction modulators in the treatment of gynecologic malignancies. Curr Treat Options Oncol 8(6):383–392. doi:10.1007/s11864-007-0051-z

    Article  PubMed  Google Scholar 

  4. Bellone S, Frera G, Landolifi G (2007) Overexpression of epidermal growth factor typr-1 receptor (EGF-R1) in cervical cancer: implications for cetuximab-mediated therapy in recurrent/metastatic disease. Gynecol Oncol 106(3):513–520. doi:10.1016/j.ygyno.2007.04.028

    Article  CAS  PubMed  Google Scholar 

  5. Kim GE, Kim YB, Cho NH, Chung HC, Pyo HR, Lee JD (2004) Synchronous co-expression of epidermal growth factor receptor and cyclooxygenase-2 in carcinomas of the uterine cervix: a potential predictor of poor survival. Clin Cancer Res 10(4):1366–1374. doi:10.1158/1078-0432.CCR-0497-03

    Article  CAS  PubMed  Google Scholar 

  6. Schlessinger J (2002) Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell 110:669–672. doi:10.1016/S0092-8674(02)00966-2

    Article  CAS  PubMed  Google Scholar 

  7. Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225. doi:10.1016/S0092-8674(00)00114-8

    Article  CAS  PubMed  Google Scholar 

  8. Fry DW, Kraker AJ, McMichael A, Ambroso LA, Nelson JM, Leopold WR (1994) A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science 265:1093–1095. doi:10.1126/science.8066447

    Article  CAS  PubMed  Google Scholar 

  9. Boschelli DH (2002) 4-Anilino-3-quinolinecarbonitriles: an emerging class of kinase inhibitors. Curr Top Med Chem 2(9):1051–1063

    Article  CAS  PubMed  Google Scholar 

  10. Bos M, Mendelsohn J, Kim YM, Albanell J, Fry DW, Baselga J (1997) PD153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptor activation and inhibits growth of cancer cells in a receptor number-dependent manner. Clin Cancer Res 3(11):2099–2106

    CAS  PubMed  Google Scholar 

  11. Marshall J (2006) Clinical implications of the mechanism of epidermal growth factor receptor inhibitors. Cancer 107(6):1207–1218. doi:10.1002/cncr.22133

    Article  CAS  PubMed  Google Scholar 

  12. Schilder RJ, Sill MW, Chen X (2005) Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecologic Oncology Group study. Clin Cancer Res 11:5539–5548. doi:10.1158/1078-0432.CCR-05-0462

    Article  CAS  PubMed  Google Scholar 

  13. Baselga J, Rischin D, Ranson M et al (2002) Phase I safety, pharmacokinetic and pharmacodynamic trial of ZD 1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected tumor types. J Clin Oncol 20:4292–4302. doi:10.1200/JCO.2002.03.100

    Article  CAS  PubMed  Google Scholar 

  14. Slomovitz BM, Coleman RL, Levenback C et al (2006) Phase I study of weekly topotecan and gefitinib in patients with platinum resistant ovarian, peritoneal or fallopian tube cancer. J Clin Oncol (2006 ASCO Annual Meeting Proceedings Part I) 24(Suppl.):5090

    Google Scholar 

  15. Hariprasad R, Kumar L, Patnaik R, Gupta A, Kumar S (2006) Maintenance therapy in epithelial ovarian cancer (EOC): could EGFR inhibitor-gefitinib be a candidate drug? A pilot study. J Clin Oncol (2006 ASCO Annual Meeting Proceedings Part I) 24(Suppl.):15046

    Google Scholar 

  16. Nicholson RI, Gee JM, Harper ME (2001) EGFR and cancer prognosis. Eur J Cancer 37(suppl 4):S9–S15. doi:10.1016/S0959-8049(01)00231-3

    Article  CAS  PubMed  Google Scholar 

  17. Sewell JM, Macleod KG, Ritchie A, Smyth JF, Langdon SP (2002) Targeting the EGF receptor in ovarian cancer with the tyrosine kinase inhibitor ZD1839 (“Iressa”). Br J Cancer 86(3):456–462. doi:10.1038/sj.bjc.6600058

    Article  CAS  PubMed  Google Scholar 

  18. Vermeij J, Teugels E, Bourgain C, Xiangming J, in’t Veld P, Ghislain V, Neyns B, De Grève J (2008) Genomic activation of the EGFR and HER2-neu genes in a significant proportion of invasive epithelial ovarian cancers. BMC Cancer 8:3

    Article  PubMed  Google Scholar 

  19. Lacroix L, Pautier P, Duvillard P, Motte N, Saulnier P, Bidart JM, Soria JC (2006) Response of ovarian carcinomas to gefitinib–carboplatin–paclitaxel combination is not associated with EGFR kinase domain somatic mutations. Int J Cancer 118(4):1068–1069. doi:10.1002/ijc.21460

    Article  CAS  PubMed  Google Scholar 

  20. Rivera F, Vega-Villegas ME, López-Brea MF (2008) Cetuximab, its clinical use and future perspectives. Anticancer Drugs 19(2):99–113

    Article  CAS  PubMed  Google Scholar 

  21. Palayekar MJ, Herzog TJ (2008) The emerging role of epidermal growth factor receptor inhibitors in ovarian cancer. Int J Gynecol Cancer 8(5):879–890. doi:10.1111/j.1525-1438.2007.01144.x

    Article  Google Scholar 

  22. Woodburn JR (1999) The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 82:241–250. doi:10.1016/S0163-7258(98)00045-X

    Article  CAS  PubMed  Google Scholar 

  23. Ciardiello F, Tortora G (2001) A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res 7:2958–2970

    CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Dr. Manjari Dimri for help in revising the manuscript.

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Authors and Affiliations

  1. Institute of Material Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Xian Nong Tan Street, Beijing, 100050, People’s Republic of China

    Jing Li, Yang Meng, Yue Liu, Zhi-Qiang Feng & Xiao-Guang Chen

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  1. Jing Li
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  2. Yang Meng
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  3. Yue Liu
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  4. Zhi-Qiang Feng
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  5. Xiao-Guang Chen
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Correspondence to Xiao-Guang Chen.

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Li, J., Meng, Y., Liu, Y. et al. F84, a quinazoline derivative, exhibits high potent antitumor activity against human gynecologic malignancies. Invest New Drugs 28, 132–138 (2010). https://doi.org/10.1007/s10637-009-9225-9

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  • DOI: https://doi.org/10.1007/s10637-009-9225-9

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