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17.06.2015

Uterine cancer experimental treatment, herpes informational brochure - How to DIY

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Abstract: Endometrial cancer is the most common gynecologic malignancy and represents a major health concern because overall five-year survival rates have not improved in the last three decades. Estrogen and progesterone are two key regulators of proliferation and differentiation in reproductive tissues, including the uterine endometrium (Graham and Clarke, 1997).
Endometrial cancer, the cause of nearly 8,000 deaths last year (2009), arises from the endometrium and is related to estrogen exposure unopposed by the differentiating effects of progesterone (Rose, 1996).
Progesterone-based therapy has long been explored as a therapeutic strategy for endometrial cancer (Figure 1). Hormonal therapy for advanced or recurrent endometrial carcinoma is not the panacea it was hoped to be following the early experiences, especially in light of the activity of chemotherapeutic agents in metastatic endometrial cancer. As described above, while progestin therapy achieves promising outcomes with early stage endometrial cancer, this therapy is only modestly effective for advanced and recurrent disease. Since endometrial cancer often has epigenetic changes, including global hypomethylation and hypermethylation of tumor suppressor genes, several preclinical studies have explored how these epigenetic modifications can be therapeutically manipulated to either promote cell death or restore sensitivity to chemotherapy.
Single or combination therapy with DNMTi and HDACi can restore expression of tumor suppressor genes in endometrial cancer cell lines, which results in reduced cell growth or activation of apoptosis (Balch et al., 2010). In summary, the molecular age has opened new avenues of treatment to enhance the effectiveness of progestin therapy for endometrial cancer.
A great deal of research demonstrates that the endometrium is extremely sensitive to hormones, and a shift in the estrogen:progesterone balance is the major cause for the development of endometrial cancer.
Estrogen delivers a pro-growth signal to the cells, which, when unchecked, leads to cancer. With respect to grade, the therapeutic efficacy of progestin has also been explored for endometrial hyperplasia, which can lead to endometrial cancer if untreated, and primary endometrial cancer. As expected, chemotherapy is associated with significant adverse effects since it targets all proliferating cells, not just cancer cells. Based on preclinical and clinical findings, several potential reasons have been postulated for the lack of complete response to progesterone with more advanced endometrial cancers, and the leading theory is that progesterone promotes gradual loss of PR expression, which would render the tumors unresponsive to further progesterone therapy (Mortel et al., 1990). Most studies adopt a combination approach to achieve maximum effect because, in addition to the individual effects of DNMTi and HDACi, the combination of these two classes of drugs is often more effective than single agent treatment.
In particular, several studies have demonstrated that this treatment strategy promotes upregulation of PR in endometrial cancer cell lines. Estrogen and progestin receptor levels as prognosticators for survival in endometrial cancer.


Metastatic endometrial cancer in lung and liver: complete and prolonged response to hormonal therapy with progestins. Progesterone regulation of activating protein-1 transcriptional activity: a possible mechanism of progesterone inhibition of endometrial cancer cell growth. Progesterone inhibits human endometrial cancer cell growth and invasiveness: down-regulation of cellular adhesion molecules through progesterone B receptors. Biphasic regulation of breast cancer cell growth by progesterone: role of the cyclin-dependent kinase inhibitors, p21 and p27(Kip1). Progesterone receptor isoform identification and subcellular localization in endometrial cancer. Megestrol and tamoxifen in patients with advanced endometrial cancer: an Eastern Cooperative Oncology Group Study (E4882). Down-regulation of the progesterone receptor by the methylation of progesterone receptor gene in endometrial cancer cells. Progesterone receptor B gene inactivation and CpG hypermethylation in human uterine endometrial cancer. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group.
Epigenetic-mediated upregulation of progesterone receptor B gene in endometrial cancer cell lines.
High response rates, a low toxicity profile, and the availability of oral medroxyprogesterone acetate (MPA, Depo-Provera) and megestrol acetate (MA, Megace) contributed to the popularization of the treatment of advanced or recurrent endometrial carcinoma with progestins.
Progestins are very effective at reversing hyperplasia, with response rates as high as 80-90%, and the overall response rate for primary endometrial cancer is 50-70% (Kim and Chapman-Davis, 2010). Both of these trials used pulses of progestin and either continual or alternating treatment with tamoxifen.
The goal was to examine the relationship between the expression of hormone receptors in advanced endometrial cancer and the clinical response.
This is especially a concern in women with endometrial cancer, who are often elderly and who have co-morbidities such as obesity, diabetes, cardiovascular disease, and who may have had previous radiation therapy.
However, in cancer, transcription of tumor suppressors is blocked by DNA methylation, including PR, and many groups have therefore explored DNMT inhibitors (DNMTi) to restore expression of these tumor suppressors.
Ishikawa H endometrial cancer cells were treated with either vehicle control (left image) or a combination of HDACi and DNMTi (right image).


This strategy might be applied at various points along the continuum of endometrial cancer prevention, primary treatment, and treatment of recurrent disease. A complete understanding of the pathways by which progesterone acts as a tumor suppressor, as well as the molecules that regulate progesterone activity, is necessary to fully achieve therapeutic efficacy with progestin in endometrial cancer.
Thus, the re-establishment of progesterone control of the endometrium in the setting of cancer has particular value and is the goal of progestin therapy in endometrial cancer. Kelley and Baker (1961) were the first to report an objective response in approximately one-third of patients with advanced endometrial cancer treated with intramuscular injections of various progestational agents. For example, GOG study 211 used MPA as a neoadjuvant non-therapeutic intervention for women who had been recently diagnosed with endometrial cancer after the initial biopsy. Based on these positive response rates, chemotherapy has become the standard antineoplastic treatment option for most women with advanced disease, though overall survival rates are similar between chemotherapy and progestin therapy.
A current hot topic in anti-cancer therapy is to restore gene expression through the use of epigenetic modulators (Balch et al., 2010), and a few studies have taken this approach with PR activity in endometrial cancer. Importantly, in preclinical experiments, treatment of endometrial cancer cell lines with the DNMTi decitabine results in PRB expression (Sasaki et al., 2001), thereby implying that use of epigenetic modulators in vivo may restore PR expression and consequently sensitivity to progestins.
With increased insight in the pathology of endometrial hyperplasia and cancer, and identification of additional molecular targets for therapy, further research and development of hormonal manipulation in endometrial carcinoma is warranted. While these drugs were initially approved for treatment of leukemia and myelodysplastic syndrome, they have also demonstrated promising clinical activity for solid tumors (Boumber and Issa, 2011). We have replicated these studies using other endometrial cancer cell lines and next-generation epigenetic modulatory drugs and detected a similar increase in PR expression (Figure 2).
This prompts the exciting possibility that even women with early stage endometrial cancer, but who wish to preserve the uterus for future childbearing, might also benefit by the addition of an epigenetic modulator to the current progestin regimens in use in the clinic. In this article, we describe one current approach to restore expression of PR at the epigenetic level in endometrial cancer. Similarly, with endometrial cancer incidence on the rise in the obese population, cancer prevention might be optimized by the proposed dual regimen of progestin plus an epigenetic modulator.




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Comments to “Uterine cancer experimental treatment”

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