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ABSTRACT: A major limitation in the treatment of cancers is the prevalence of chemoresistant tumors. Chemotherapy agents induce cell death by activating apoptosis. However, most cancer cells express high levels of antiapoptotic proteins and, hence, are chemoresistant. Phenoxodiol, a novel isoflavone derivative, has been shown to induce apoptosis both in vitro and in vivo, even in chemoresistant cancer cells. In addition, phenoxodiol has been shown to chemosensitize resistant cancer cells to commonly used chemotherapy agents, such as carboplatin and paclitaxel. This review will discuss the characterization of phenoxodiol's molecular mechanism and its current state in the clinic.
Future Oncology 09/2008; 4(4):475-82. · 3.16 Impact Factor
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ABSTRACT: Early identification of chemoresistance in patients with ovarian cancer is of utmost importance in order to provide them with the most appropriate therapy. Recently, we described the expression of MyD88 in ovarian cancer cells that were resistant to the cytotoxic agent paclitaxel. In addition to chemoresistance, in MyD88 positive ovarian cancer cells, paclitaxel stimulates growth and production of proinflammatory cytokines. The objective of this study was to determine the correlation of MyD88 expression in primary and recurrent epithelial ovarian cancers with the response to carboplatin and paclitaxel combination chemotherapy.
Tumors are heterogeneous structures that contain different cell populations, thus rendering the identification of specific tumor markers difficult. Using laser capture microdissection, pure cancer cells were isolated from ovarian malignant tumors that were obtained from 20 patients at the time of surgery. The microdissected cells were evaluated for the expression of MyD88, FasL, and XIAP by western blot analysis.
Protein expression was observed in samples containing as low as 500 cells. The results were correlated with the clinical course of those patients. It was evident that MyD88 expression in ovarian cancer cells accurately predicts a poor response to paclitaxel chemotherapy as shown by a short progression-free interval and overall survival.
We describe for the first time a molecular approach to identify paclitaxel chemoresistance. Toxicity from agents without therapeutic benefit can be avoided by identifying those patients who will not respond to a specific agent. Molecular markers will enable us to design individualized treatments and improve overall survival.
The Yale journal of biology and medicine 01/2007; 79(3-4):153-63.
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ABSTRACT: To investigate weekly topotecan in heavily pretreated patients with recurrent ovarian cancer.
The records of patients with recurrent epithelial ovarian cancer who were treated with weekly topotecan after failure of > or =1 prior regimen were reviewed. Patients received topotecan (median starting dose approximately 2.5 mg/m(2)) on days 1, 8, and 15 of a 28-day cycle. Antitumor response was assessed after 2 cycles by serial CA-125 levels.
Thirty-five heavily pretreated patients received a mean of 5 cycles of topotecan (range, 1-13 cycles). Thirty-two patients had definable platinum sensitivity (16 sensitive, 8 resistant, 8 refractory). Median age was 56 years. A total of 177 cycles (534 weeks) of topotecan was administered. Hematologic toxicity was generally mild, and no grade 4 toxicities were observed. Grade 3 hematologic toxicity, including leukopenia, neutropenia, thrombocytopenia, and anemia, was observed in 2, 2, 1, and 0 patients, respectively. No patients experienced grade 3 or 4 nonhematologic toxicity. Based on serial CA-125 measurements, there were 1 (3%) complete and 5 (15%) partial responses, with 1 of the partial responses in a patient with platinum-refractory disease. Stable disease was reported in 13 (38%) patients, including 5 patients with platinum-resistant/refractory disease.
Weekly topotecan demonstrates activity and is well tolerated compared with historical data with the standard 5-day schedule. Higher doses may be warranted because of the high tolerability shown for weekly topotecan. Weekly topotecan may be an appropriate treatment option for patients with recurrent ovarian cancer, especially heavily pretreated patients who might require dosing schedules with improved tolerability.
Gynecologic Oncology 08/2005; 98(2):242-8. · 3.89 Impact Factor
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ABSTRACT: The term 'minimal uterine serous carcinoma' has been proposed to include serous carcinomas with invasion limited to the endometrium (superficial serous carcinoma), and those without stromal invasion (intraepithelial serous carcinoma or endometrial intraepithelial carcinoma). Both lesions display similar cytological and immunohistochemical profiles of a typical invasive serous carcinoma with a high nuclear grade and an overexpression of mutant p53 protein. We studied the clinicopathologic features of 40 cases of minimal uterine serous carcinoma. All patients were postmenopausal and underwent hysterectomy and surgical staging procedures. There were nine cases of intraepithelial serous carcinoma and 31 cases of superficial serous carcinoma. Five intraepithelial serous carcinomas and 16 superficial serous carcinomas exclusively involved an endometrial polyp. A total of 18 minimal uterine serous carcinomas also involved, in addition to a polyp, the endometrium proper in the form of intraepithelial serous carcinoma (13 cases) and superficial serous carcinoma (five cases). Overall, minimal uterine serous carcinomas were found to involve an endometrial polyp in 88% of the cases (35/40) and were confined to the polyp in 53% (21/40). Extrauterine tumors were present in 45% of the cases (18/40). In all, 22 patients with tumor limited to their uteri demonstrated an overall survival of 94% (2-73 months of follow-up). Eight of 18 patients with extrauterine tumors died of their malignancy (1.5-62 months of follow-up). In conclusion, a significant majority of minimal uterine serous carcinomas involve an endometrial polyp. Complete surgical staging is important to predict the prognosis. When the lesion is confined to an endometrial polyp and/or the endometrium proper, the clinical outcome is excellent.
Modern Pathology 02/2005; 18(1):75-82. · 4.79 Impact Factor
