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      Emerging Biological Treatments for Uterine Cervical Carcinoma

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          Abstract

          Cervical cancer is the third most common cancer worldwide, and the development of new diagnosis, prognostic, and treatment strategies is a major interest for public health. Cisplatin, in combination with external beam irradiation for locally advanced disease, or as monotherapy for recurrent/metastatic disease, has been the cornerstone of treatment for more than two decades. Other investigated cytotoxic therapies include paclitaxel, ifosfamide and topotecan, as single agents or in combination, revealing unsatisfactory results. In recent years, much effort has been made towards evaluating new drugs and developing innovative therapies to treat cervical cancer. Among the most investigated molecular targets are epidermal growth factor receptor and vascular endothelial growth factor (VEGF) signaling pathways, both playing a critical role in cervical cancer development. Studies with bevacizumab or VEGF receptor tyrosine kinase have given encouraging results in terms of clinical efficacy, without adding significant toxicity. A great number of other molecular agents targeting critical pathways in cervical malignant transformation are being evaluated in preclinical and clinical trials, reporting preliminary promising data.

          In the current review, we discuss novel therapeutic strategies which are being investigated for the treatment of advanced cervical cancer.

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            Association of human papillomavirus types 16 and 18 E6 proteins with p53.

            Human papillomavirus type 16 (HPV-16) is a DNA tumor virus that is associated with human anogenital cancers and encodes two transforming proteins, E6 and E7. The E7 protein has been shown to bind to the retinoblastoma tumor suppressor gene product, pRB. This study shows that the E6 protein of HPV-16 is capable of binding to the cellular p53 protein. The ability of the E6 proteins from different human papillomaviruses to form complexes with p53 was assayed and found to correlate with the in vivo clinical behavior and the in vitro transforming activity of these different papillomaviruses. The wild-type p53 protein has tumor suppressor properties and has also been found in association with large T antigen and the E1B 55-kilodalton protein in cells transformed by SV40 and by adenovirus type 5, respectively, providing further evidence that the human papillomaviruses, the adenoviruses, and SV40 may effect similar cellular pathways in transformation.
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              Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents.

              Wee1 is a tyrosine kinase that phosphorylates and inactivates CDC2 and is involved in G(2) checkpoint signaling. Because p53 is a key regulator in the G(1) checkpoint, p53-deficient tumors rely only on the G(2) checkpoint after DNA damage. Hence, such tumors are selectively sensitized to DNA-damaging agents by Wee1 inhibition. Here, we report the discovery of a potent and selective small-molecule inhibitor of Wee1 kinase, MK-1775. This compound inhibits phosphorylation of CDC2 at Tyr15 (CDC2Y15), a direct substrate of Wee1 kinase in cells. MK-1775 abrogates G(2) DNA damage checkpoint, leading to apoptosis in combination with DNA-damaging chemotherapeutic agents such as gemcitabine, carboplatin, and cisplatin selectively in p53-deficient cells. In vivo, MK-1775 potentiates tumor growth inhibition by these agents, and cotreatment does not significantly increase toxicity. The enhancement of antitumor effect by MK-1775 was well correlated with inhibition of CDC2Y15 phosphorylation in tumor tissue and skin hair follicles. Our data indicate that Wee1 inhibition provides a new approach for treatment of multiple human malignancies.
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                Author and article information

                Journal
                J Cancer
                J Cancer
                jca
                Journal of Cancer
                Ivyspring International Publisher (Sydney )
                1837-9664
                2014
                5 January 2014
                : 5
                : 2
                : 86-97
                Affiliations
                1. Department of Medical Oncology B, Regina Elena National Cancer Institute, V Elio Chianesi 53, 00144, Rome, Italy
                2. Department of Gynecologic Oncology, Regina Elena National Cancer Institute, V Elio Chianesi 53, 00144, Rome, Italy
                3. HPV Unit, Regina Elena National Cancer Institute, V Elio Chianesi 53, 00144, Rome, Italy
                4. Department of Gynaecology and Obstetrics, “La Sapienza” University, V Policlinico 155, 00161, Rome, Italy
                5. Department of Medical-Surgical Sciences and Biotechnologies, “La Sapienza” University of Rome, Oncology Unit, C.so della Repubblica, 04100, Latina, Italy
                6. Scientific Direction, Regina Elena National Cancer Institute, V Elio Chianesi 53, 00144, Rome, Italy
                7. Department of Radiation Oncology, Regina Elena National Cancer Institute,V Elio Chianesi 53, 00144, Rome, Italy
                8. Laboratory of Virology, Regina Elena National Cancer Institute, V Elio Chianesi 53, 00144, Rome, Italy
                Author notes
                ✉ Corresponding author: Patrizia Vici, MD, Department of Medical Oncology B - Regina Elena National Cancer Institute, V Elio Chianesi 53, 00144, Rome, Italy. E-mail: pvici@ 123456ifo.it ; Tel.: 00390652665584; Fax: 00390652665075

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                jcav05p0086
                10.7150/jca.7963
                3909763
                24494026
                aab14282-8d30-4a4a-8906-77d7aeccf1cc
                © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
                History
                : 23 October 2013
                : 9 December 2013
                Categories
                Review

                Oncology & Radiotherapy
                tyrosine kinase inhibitors.,therapy,molecular targeted agents,clinical trials,advanced cervical cancer

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