Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several general conclusions are beginning to emerge from the series of prospective trials in the treatment of ovarian cancer. Combination chemotherapy continues to demonstrate higher overall response rates and higher complete remission rates than single alkylating agents, although in some studies survival is not significantly different. Nevertheless, long-term disease-free survivals, although uncommon, are more frequent with combinations, particularly when the dose intensity of the combination is adequate. Although CAP is the most commonly used combination, evidence continues to suggest that cyclophosphamide/cisplatin alone may be equivalent. Several studies have incorporated alkylating agent maintenance into their clinical trials and each reports acute leukemic complications. In light of the absence of a major contribution for this approach, alkylating agent maintenance in ovarian cancer should not be encouraged. Several studies this year emphasize the discouraging results associated with the use of total abdominal radiation therapy post-induction chemotherapy even with patients with minimal or no residual disease. In light of the publications this year and of previously published studies, this approach, although based on sound rationale, appears to be of limited benefit. Salvage chemotherapy, in general, has been unsatisfactory. The 2 interesting reports this year were the activity of low-dose mitomycin C and the potential utility of VP-16/cisplatin combinations in a salvage setting. In cervix carcinoma, trials have documented significant activity for the new drugs, carboplatin (28% response) and ifosfamide (30%), but each has significant side effects. Whether these will prove more active than cisplatin or whether they may be used in combination is unresolved. The continued investigation into the use of radiation sensitizers in cervical carcinoma is of interest and several studies using weekly low-dose cisplatin have established the feasibility of this approach, although long-term survival benefits have not yet been documented. In endometrial carcinoma, epidemiologic studies continue to define the role of postmenopausal estrogens in endometrial carcinoma risk. This year a Swedish study documents a smaller overall risk from estrogen treatment, perhaps related to a substantially lower use of conjugated estrogens in that country. Combination chemotherapy continues to show some activity, although the contribution of combinations in excess of the single agent activity of doxorubicin is still poorly documented. One study does demonstrate significant activity for the commonly used CAP regimen with an overall response rate of 56% and 28% complete remissions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Gynecologic malignancies. 285 38

The epipodophyllotoxin derivatives, etoposide (VP-16) and teniposide (VM-26), are highly lipophilic anticancer drugs supplied with novel commercial solvent systems. A BALB/c mouse skin toxicity model was used to evaluate the ulcerative potential of intradermal (ID) VP-16 and its lipophilic solvent system along with the main ingredient of the VM-26 solvent, polyethoxylated castor oil (PECO). ID VP-16 caused dose-dependent ulceration following 0.17 mg, 0.33 mg (50 mg/M2) or 1.0 mg (150 mg/M2). Both normal saline (0.05 ml ID) and hyaluronidase (7.5 u ID) were effective as local VP-16 antidotes, presumably by diluting out the extravasated drug. The VP-16 solvent alone was as toxic as the 1.0 mg (undiluted) ID VP-16 injection. ID PECO was mildly ulcerative in mouse skin. When given to P-388 lymphocytic leukemia-bearing mice, both VP-16 (24 mg/kg IP for 3 doses) and VM-26 (8 mg/kg IP for 2 doses) were active, producing increased life spans (ILS) of 160% and 90%, respectively. The solvents, given IP at the same schedule, did not increase or decrease the life span of tumor-bearing mice, but did increase morbidity. In an in vitro human tumor clonogenic assay (WiDr colon carcinoma and HEC-1A endometrial carcinoma in soft agar), both VP-16 and VM-26 showed moderate to complete inhibition of tumor colony forming units (TCFUs) by continuous exposure. 1-h drug exposures were marginally active at reducing TCFUs. None of the epipodophyllotoxin diluents at clinical concentrations reduced TCFUs. At very high concentrations, both epipodophyllotoxins were cytotoxic. They were more effective at reducing TCFUs when plated as a continuous exposure rather than a 1-h exposure.
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PMID:Skin ulceration potential without therapeutic anticancer activity for epipodophyllotoxin commercial diluents. 667 64

Forty-nine consecutive patients with metastatic or recurrent endometrial carcinoma were treated with a monthly combination chemotherapy consisting of VP 16-213 80 mg/m2 i.v. Days 1-3, 5-fluorouracil (5-FU) 600 mg/m2 i.v. Days 1-3, and cisplatin 35 mg/m2 i.v. Days 1-3. The objective response rate was 41% (95% CI, 27-54%) with 14.3% complete responses. The median survival duration was 14 months. The median response duration was 12 months. The estimated median survival for responders was 20 months. Three patients are still free of disease 5 years after treatment. The major toxic effects were myelosuppression (less than 25% of grade III and IV leucopenia, and 14% grade III and IV thrombocytopenia). Grade III peripheral neuropathy was observed in five patients. Cisplatin administration had to be stopped due to renal toxicity in six patients. No treatment-related deaths occurred. The combination of etoposide, 5 fluorouracil, and cisplatin is an effective regimen with an acceptable toxicity in patients with recurrent or metastatic endometrial carcinoma.
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PMID:Treatment of advanced or recurrent endometrial carcinoma with combination of etoposide, cisplatin, and 5-fluorouracil: a phase II study. 855 29

We evaluated the effects of a combined chemotherapy regimen on endometrial carcinoma in 14 patients with lymph node metastasis. After surgery, the patients were treated with 3 cycles of chemotherapy (PVP regimen) every 4 weeks. The PVP regimen consisted of 75 mg/m2 cisplatin on day 1, 40 mg/m2 pirarubicin (P) on day 1, and 75 mg/m2 etoposide (VP-16: V) on days 2, 3 and 4. The effect of adjuvant chemotherapy was evaluated based on progression-free survival (PFS), overall survival (OS), and adverse effects. The 5-year PFS rate was 52% [95% confidence interval (CI), 10-94%], and the 5-year OS rate was 50% (95% CI, 16-84%). The major toxicity was myelosuppression. One hundred percent of patients had neutropenia above grade 3, but all recovered from myelosuppression. PVP therapy may be an effective adjuvant therapy for endometrial carcinoma patients with lymph node metastasis used as an alternative to radiation therapy.
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PMID:Postoperative adjuvant chemotherapy with cisplatin, etoposide, and pirarubicin for endometrial carcinoma patients with lymph node metastasis: A pilot study. 1094 43

We have evaluated the growth inhibitory effects of paclitaxel alone or irinotecan (CPT-11) alone and their combined effects with other drugs on human endometrial cancer cell lines. IC50 doses of paclitaxel (Tx), SN-38 (active metabolite of CPT-11; 7-ethyl-10-hydroxycamptothecin) and cisplatin, including other drugs which have been used for treatment of patients with endometrial cancer, were examined using five human endometrial cancer cell lines (Ishikawa, HEC-1A, HEC-50B, HEC-59 and HEC-108). When in vitro sensitivity was defined IC50 lower than 10% of the peak plasma concentration (PPC), all endometrial cancer cell lines were sensitive to paclitaxel and three of five endometrial cancer cell lines were sensitive to SN-38, whereas cisplatin was not active against any endometrial cancer cell lines used in this study. Regarding the other drugs, aclarubicin (ACR) and actinomycin D (ACD) were active against four of five endometrial cancer cell lines, etoposide (VP-16) and pirarubicin (THP) against two, and 5-fluorouracil (5-FU) against only one, while ifosfamide (4-OHIFO) was not active against any endometrial cancer cell lines. When combined effects of paclitaxel or SN-38 with other one drug were determined by the median-effect analysis, paclitaxel followed by cisplatin resulted in synergistic effects to all endometrial cancer cell lines. Paclitaxel followed by SN-38 also had synergistic effects to four cell lines. Sequential but not simultaneous administration of taxol and THP-adriamycin showed synergistic effects to three cell lines. In combinations of SN-38 with other drugs, simultaneous administration of SN-38 and cisplatin resulted in synergistic effects to all cell lines. It is noteworthy that ACD followed by SN-38 showed synergistic effects to all cell lines, and simultaneous treatment of ACD and SN-38 or SN-38 followed by ACD also resulted in synergistic effects to three cell lines. THP-adriamycin followed by SN-38 had synergistic effects to four cell lines. The present quantitative data analysis for synergism provides a basis for a rational design of clinical protocols for combination chemotherapy in patients with endometrial cancer of the uterus.
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PMID:In vitro sensitivity of human endometrial cancer cell lines to paclitaxel or irinotecan (CPT-11) in combination with other aniticancer drugs. 1103 61

Endometrial cancer is the most common invasive gynecologic malignancy but the molecular mechanisms underlying its onset and progression are poorly understood. Paradoxically, endometrial tumors exhibit increased apoptosis, correlating with disease progression and poor patient prognosis. Endometrial tumors also show altered activity and expression of protein kinase C (PKC) isoforms, implicated in the regulation of programmed cell death; however, PKC modulation of apoptosis in endometrial cancer cells has not been investigated. We detected nine out of ten PKC isoforms in Ishikawa endometrial cancer cell lines, and demonstrated expression of both PKCalpha and delta in human endometrial tumors. To determine the functional roles of PKCalpha and delta in apoptosis in endometrial cancer, Ishikawa cells were treated with selective PKC inhibitors or adenoviral constructs encoding wild-type or isoform-specific, dominant-negative mutants. Apoptosis was assessed by DNA fragmentation and caspase-mediated poly-(ADP-ribose)-polymerase cleavage. The inhibition of PKCdelta suppressed etoposide-induced apoptosis, while overexpression of PKCdelta enhanced it. In contrast, inhibition of PKCalpha elevated basal levels of apoptosis and potentiated etoposide-induced cell death. Etoposide treatment also selectively activated PKCdelta, but resulted in both cytosolic translocation and decreased activity of PKCalpha. A fraction of PKCdelta also underwent caspase-dependent cleavage, in response to etoposide. Our results suggest that changes in apoptosis and PKC expression in endometrial cancer are mechanistically linked, such that PKCdelta is required for DNA damage-induced apoptosis, while PKCalpha mediates a survival response. Thus, PKCalpha and delta expression and signaling may be important in endometrial tumorigenesis and could serve as potential prognostic indicators and/or novel targets for therapeutic intervention.
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PMID:Endometrial cancer cell survival and apoptosis is regulated by protein kinase C alpha and delta. 1715 69

c-Jun N-terminal kinases (JNKs) are important regulators of cell proliferation and apoptosis that have been implicated in tumorigenesis. We investigated the role of JNKs in apoptotic responses in Ishikawa and HEC-50 cells, models of type I and type II endometrial cancer, respectively. Etoposide treatment or UV irradiation resulted in sustained activation of JNK, correlating with the induction of apoptosis. Inhibition of JNK, or MAP kinase kinase 4 (MKK4), selectively suppressed apoptotic responses in both Ishikawa and HEC-50 cells. Knockdown of protein kinase C delta (PKCdelta) also attenuated apoptosis in endometrial cancer cells and inhibited the sustained, UV-mediated JNK activation in HEC-50, but not Ishikawa cells. Etoposide-induced JNK phosphorylation was unaffected by PKCdelta knockdown, implying that JNK can regulate apoptosis by PKCdelta-dependent and independent pathways, according to stimulus and cell type. Thus, expression and activity of JNK and PKCdelta in endometrial cancer cells modulate apoptosis and sensitivity to chemotherapeutic agents and may function as tumor suppressors in the endometrium.
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PMID:c-Jun N-terminal kinase regulates apoptosis in endometrial cancer cells. 1942