The administration and combination of a variety of chemotherapeutic agents for treatment of advanced or recurrent uterine cancer of different histologies is under current debate. Mixed Mullerian Tumors (MMTs), which contain both adenocarcinoma and sarcoma components, are the most rate histologic type and it is therefore difficult to conduct clinical trials to determine if they should be treated like endometrial adenocarinomas or like sarcomas. Flexible Heteroarotionoids (Flex-Hets) are a promising class of anti-cancer drugs with low toxicity that have demonstrated activity against a wide variety of cancer types, but their efficacy in uterine cancers is unknown. The objective of this study was to determine if cell lines established from endometrial carcinoma (HEC-1-A), uterine sarcoma (SK-UT-1) and MMT (MES-SA) cancers exhibit differential sensitivities to cisplatin, carboplatin, paclitaxel, docetaxel, doxorubicin and SHetA2, if SHetA2 can enhance sensitivity to the chemotherapeutic drugs and if SHetA2 exhibits a differential effect on uterine cancer cells in comparison to normal endometrial cells using a cytotoxicity assay. These cell lines did not differ in their sensitivities to platinum or taxel drugs. Doxorubicin was active against the sarcoma but not the adenocarcinoma or MMT cell lines. SHetA2 decreased the survival of all three cell lines, but did not enhance their sensitivities to the chemotherapeutic agents. Two of the three uterine cancer cell lines were more sensitive to SHetA2 in comparison to normal endometrial cells. In conclusion, doxorubicin appears to have a greater effect against sarcoma than other uterine histology types. SHetA2 is affective against uterine cancer cell lines, but does not enhance their sensitivities to chemotherapeutic agents.
Despite the enormous promise that targeted therapies hold for patients with gynecologic malignancies, it is far too early to recommend any targeted therapy outside of a clinical trial. There remains considerable work to be done before targeted therapies will have a significant role in this patient population. We have learned that different tumor types express different targets, but that the mere expression of a target does not necessarily correlate with benefit from the use of the targeted agent. No less important is the challenge of determining how these agents should be studied in clinical trials, and what constitutes an active agent. To document efficacy, targeted agents would hopefully produce response (ie, shrinkage of measurable tumor), but as cytostatic agents, the ability to delay tumor growth or slow the development of symptoms would be clinically important. Combining targeted therapies with cytotoxic agents, radiation, or other targeted therapies may be important areas for study, but it is essential to demonstrate the additive or synergistic effect of the targeted therapy to an already established active one. This review covers strategies used to develop targeted agents, reviews available targeted therapies, and suggests potential roles in the treatment of gynecologic cancers.
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