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Gynecological Cancer Therapeutic Mechanisms of Treatment in Cervical and Vaginal Cancer Charles A Kunos, MD, PhD Director of Gynecologic Radiation Oncology, Department of Radiation Oncology, University Hospitals Cleveland Abstract Cervical and vaginal cancers remain serious health problems. Worldwide, more than 530,000 women annually are diagnosed with these diseases, with most new incident cases occurring in nations with limited health resources and underdeveloped screening programs. For women whose disease is too bulky or widespread for surgery, radiochemotherapy should be looked upon as the standard of care. Randomized clinical trials have indicated that radiochemotherapy strategies that disrupt the repair of damaged DNA are key to the management of advanced stage cervical and vaginal cancers. Here, from a viewpoint of cancer cell molecular biology, treatments for advanced stage cervical and vaginal cancers are discussed. Keywords Cervical cancer, vaginal cancer, ribonucleotide reductase, radiochemotherapy, gemcitabine, hydroxyurea, triapine Disclosure: The author has no conflicts of interest to declare. Received: December 16, 2011 Accepted: January 3, 2012 Citation: Oncology & Hematology Review, 2012;8(1):55–60 Correspondence: Charles A Kunos, MD, PhD, Department of Radiation Oncology, University Hospitals of Cleveland, 11100 Euclid Avenue, LTR 6068 Cleveland, Ohio 44106. E: Cervical and vaginal cancers remain grave health problems worldwide. While structured screening programs based on the Papinicolaou exfoliative cytology smear have lowered the incidence for invasive disease and thus mortality attributed to cervical and vaginal cancer, 1,2 these diseases are still the leading causes of life years lost to cancer in nations poor in health resources. 3 The international stage classifications for cancers of the uterine cervix and vagina were revised recently by the International Federation of Gynecology and Obstetrics (FIGO). 4,5 Often, cervical and vaginal cancers are lumped together for the purposes of testing therapeutic hypotheses in clinical trials. 6 The treatment strategies described in this article are germane to both diseases, with subtleties in radiation therapy and brachytherapy acknowledged in other work. 6 Cervical or vaginal cancer disease of bulk greater than 4 cm raises the hazard for disease spread to other pelvic tissues and organs, rendering surgery with the intent to cure challenging. Radiochemotherapy in these scenarios has been met with considerably more success. 7–17 Clinical trials have publicized therapeutic gains that occur when radiation sterilizes pelvic disease and is aided in this effort by co-administered chemotherapies with both local and systemic cytotoxic and anticancer biologic effects. Contemporary regimens of radiochemotherapy are discussed for the treatment of women with cervical and vaginal cancers, especially as radiochemotherapy aims to manipulate the ribonucleotide reductase (RNR)-mediated deoxynucleotide triphosphate (dNTP) supply needed for DNA damage repair. Reviewed human translational clinical trials support this notion. © TOUCH BRIEFINGS 2012 Disrupted Deoxynucleotide Production and Salvage in Cervical and Vaginal Cancers A primary cause of cervical and vaginal cancers is human papillomavirus (HPV), a virus often acquired by sexual activity. 18–21 Many HPVs are associated with anogenital neoplasia, with types 16, 18, 31, 35, 39, 45, 51, 52, 56, and 58 leading to most invasive cancers. 18 To hone one’s thinking about radiochemotherapeutic strategies for cervical and vaginal cancers, it is practical to discuss HPV pathophysiology and the means by which the virus initially hijacks cervical and vaginal cell machinery for dNTP production (see Figure 1). HPV contains closed-circular, double-stranded DNA. 22 Eight open genome reading frames program early translation of six proteins (E1, E2, and E4–E7) and late translation of two proteins (L1 and L2) for multiplication of viral copy number in cells. 22 For viral genome replication, HPV interrupts host-cell mechanisms of cell-cycle termination. In doing so, HPV-E6 binds to the ‘superintendent’ p53 protein, prompts its elimination, and thus lifts molecular barriers halting cell-cycle transit through a G1/S cell-cycle restriction checkpoint. 23–25 At the same time, HPV-E7 removes restrictions linked to the retinoblastoma protein through a proteosome-dependent degradation pathway. 26 This HPV-E7-effect promotes E2F activation, 27 which turns on S-phase replication proteins responsible for normal host-cell gene duplication including subunits of RNR. The far-reaching effects of HPV proteins that supersede cell-cycle checkpoints increase the tendency to oncogenic phenotypes. 22 Current HPV biology, therefore, entices investigators to exploit pharmacologic means of limiting 2’-deoxyribonucleoside diphosphate (dNDP) 55