Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In 44 ovarian cancers, CD44 variant (CD44v) expression was investigated immunohistochemically using a variant-specific polyclonal antibody. Patients with CD44v-positive carcinomas had a significantly shorter disease-free survival than patients with CD44v-negative tumors. Overall survival was also significantly reduced for stages III and IV of the International Federation of Gynecology and Obstetrics. Furthermore, a highly significant inverse correlation was observed between CD44v expression and preoperative platelet count. Urinary neopterin concentration, a marker of cell-mediated immunostimulation, did not differ between CD44v-positive and -negative ovarian cancer patients. Moreover, in seven ovarian carcinoma cell lines, modulation of CD44v expression was analyzed by living cell radioimmunoassay. Interferon-alpha, interferon-gamma, tumor necrosis factor, transforming growth factor-beta, all-trans retinoic acid and cisplatin did not affect CD44v expression.
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PMID:Prognostic value of CD44 splice variant expression in ovarian cancer. 754 67

Well-designed and conducted Phase II clinical trials are very important to cancer chemoprevention drug development. Three critical aspects govern the design and conduct of these trials--well-characterized agents, suitable cohorts, and reliable biomarkers for measuring efficacy that can serve as surrogate endpoints for cancer incidence. Requirements for the agent are experimental or epidemiological data showing chemopreventive efficacy, safety on chronic administration, and a mechanistic rationale for the chemopreventive activity observed. Agents that meet these criteria for chemoprevention of cervical cancer include antiproliferative drugs (e.g., 2-difluoromethylornithine), retinoids, folic acid, antioxidant vitamins and other agents that prevent cellular oxidative damage. Because of the significant cervical cancer risk associated with human papilloma virus (HPV) infection, agents that interfere with the activity of HPV products may also prove to be effective chemopreventives. In endometrium, unopposed estrogen exposure has been associated with cancer incidence. Thus, pure antiestrogens and progestins may be chemopreventive in this tissue. Ovarian cancer risk is correlated to ovulation frequency; therefore, oral contraceptives are potentially chemopreventive in the ovary. Recent clinical observations also suggest that retinoids, particularly all-trans-N-4-hydroxyphenylretinamide, may be chemopreventive in this tissue. The cohort should be suitable for measuring the chemopreventive activity of the agent and the intermediate biomarkers chosen. In the cervix, patients with cervical intraepithelial neoplasia (CIN) and in endometrium, patients with atypical hyperplasia, fit these criteria. Defining a cohort for a Phase II trial in the ovary is more difficult. This tissue is less accessible for biopsy; consequently, the presence of precancerous lesions is more difficult to confirm. The criteria for biomarkers are that they fit expected biological mechanisms (i.e., differential expression in normal and high-risk tissue, on or closely linked to the causal pathway for the cancer, modulated by chemopreventive agents, and short latency compared with cancer), may be assayed reliably and quantitatively, measured easily, and correlate to decrease cancer incidence. They must occur in sufficient incidence to allow their biological and statistical evaluation relevant to cancer. Since carcinogenesis is a multipath process, single biomarkers are difficult to validate as surrogate endpoints, perhaps appearing on only one or a few of the many possible causal pathways. Panels of biomarkers, particularly those representing the range of carcinogenesis pathways, may prove more useful as surrogate endpoints. It is important to avoid solely on biomarkers that do not describe cancer but represent isolated events that may or may not be on the causal pathway or otherwise associated with carcinogenesis. These include markers of normal cellular processes that may be increased or expressed during carcinogenesis. Chemoprevention trials should be designed to evaluate fully the two or three biomarkers that appear to be the best models of the cancer. Additional biomarkers should be considered only if they can be analyzed efficiently and the sample size allows more important biomarkers to be evaluated completely. Two types of biomarkers that stand out regarding their high correlation to cancer and their ability to be quantified are measures of intraepithelial neoplasia and indicators of cellular proliferation. Measurements made by computer-assisted image analysis that are potentially useful as surrogate endpoint biomarkers include nuclear polymorphism comprising nuclear size, shape (roundness), and texture (DNA distribution patterns); nucleolar size and number of nucleoli/nuclei; DNA ploidy, and proliferation biomarkers such as S-phase fraction and PCNA...
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PMID:Strategies for phase II cancer chemoprevention trials: cervix, endometrium, and ovary. 874 72

More than 90% of epithelial ovarian cancers arise from single cells. Malignant transformation can be associated with a number of molecular alterations including upregulation of tyrosine kinases and phosphatases, physiologic activation o ras, mutation of p53, amplification of myc, and increased activity of matrix metalloproteinases 2 and 9. Proliferation of transformed epithelial cells can be enhanced through the persistence of autocrine growth stimulation by TGF-alpha, loss of autocrine growth inhibition by TGF-beta, as well as paracrine growth stimulation by macrophage derived cytokines and OCAF, a novel lyso-phospholipid. Ascites tumor cells retain responsiveness to growth inhibition by TGF-beta which induces apoptosis in malignant ovarian epithelial cells, but not in normal ovarian surface epithelium. Proliferation of surface epithelial cells following ovulation may contribute to the pathogenesis of ovarian cancer. Use of oral contraceptives that suppress ovulation has been associated with reduced risk of ovarian cancer in later life. Retinoids also deserve further evaluation for chemoprevention. Treatment with fenretinide was associated with decreased incidence of ovarian cancer. Additive or synergistic inhibition of ovarian tumor cell proliferation has been observed with TGF-beta in combination with all-trans-retinoic acid. Early detection of ovarian cancer could improve survival. Transvaginal sonography (TVS) and serum markers such as CA-125 have been evaluated in multiple clinical trials. The former lacks adequate specificity, whereas the latter is not sufficiently sensitive. Use of multiple serum markers can improve sensitivity. A combination of CA-125, M-CSF and OVX-1 has detected > 95% of Stage I ovarian cancers. If similar results are obtained with different data sets, multiple serum markers could be used to trigger the performance of TVS, providing a potentially cost effective screening strategy. Prospective trials will be required to demonstrate that screening for early stage ovarian actually impacts on survival.
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PMID:Molecular approaches to prevention and detection of epithelial ovarian cancer. 874 99

Comparison of the adherent growth inhibition of NIH:OVCAR-3 ovarian cancer cells by retinoid receptor class-selective and subtype-selective compounds with their receptor binding affinities and transcriptional activation activities indicated no correlation for RAR alpha and RAR gamma although both receptors are present. Retinoids that activated RXR alpha inhibited cell growth in the range as all-trans-retinoic acid and 9-cis-retinoic acid. The most potent inhibitor was 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN), which has been found to inhibit breast and lung cancer and leukemia cell growth and induce cancer cell apoptosis through a pathway independent of the retinoid receptors.
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PMID:Effects of receptor class- and subtype-selective retinoids and an apoptosis-inducing retinoid on the adherent growth of the NIH:OVCAR-3 ovarian cancer cell line in culture. 909 72

We have used conformationally restricted retinoids to investigate the role of individual RAR subtypes and RXR in mediating the growth response of ovarian tumor cells to retinoids. Our results show that treatment of all-trans-RA-sensitive CAOV-3 cells with retinoids that bind and activate a single RAR or RXR led to a partial inhibition of growth. Treatment of all-trans-RA- resistant SKOV-3 cells did not alter growth. Maximum inhibition of growth, comparable to that observed following treatment with natural retinoids such as all-trans-RA and 9-cis-RA, was obtained only following treatment with a combination of an RAR-selective compound and an RXR-selective one. These results suggest that activation of both RAR and RXR classes is required in order to obtain maximum inhibition of ovarian tumor cell growth by retinoids. In addition, one compound, AHPN, was found to inhibit both RA-sensitive CAOV-3 and RA-resistant SKOV-3 cells. Further study of the effects of this retinoid showed that AHPN acts through an apoptotic pathway. Taken together, our results suggest that retinoids may serve as effective anti-proliferative agents in the treatment of ovarian cancer.
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PMID:Effects of conformationally restricted synthetic retinoids on ovarian tumor cell growth. 951 63

Ovarian cancer has a poor prognosis due to the frequent appearance of a drug-resistant state. An alternative therapeutic approach may lie in combinations of conventional chemotherapeutic agents with new classes of drug, such as interferons (IFN) and differentiation-inducing agents. There is clinical evidence that both IFN-alpha2a-all-trans retinoic acid (ATRA) and IFN-alpha2a-cisplatin have significant activities on growth of malignant cells, cell differentiation or programmed cell death in solid tumors. In order to throw more light on the cellular basis of these findings and to optimize a schedule of such drug combinations, we examined the cytotoxic effects of various combinations on five human ovarian carcinoma cell lines. The experiments were based on a clonogenic assay on plastic. The different cell lines exhibited different sensitivities to the three drugs tested. Using the cell line most sensitive to these drugs, we then examined the effect of different sequences of two drug combinations. We observed a potentiation after pretreatment with ATRA followed by IFN-alpha2a and ATRA or after pretreatment with IFN-alpha2a followed by IFN-alpha2a and cisplatin. Using this schedule of administration, cytotoxic interactions between the two drugs were investigated by median effect analysis. Synergism or antagonism were observed depending on the intrinsic sensitivity of the cell line to the first drug and the concentrations used. The magnitude of these interactions was found to be influenced by the cellular sensitivity to the second drug. These results show that schedules of drug combinations are not easy to design and may help account for the various failures and the discrepant effects observed in clinical trials.
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PMID:Cytotoxic effect of interferon-alpha2a in combination with all-trans retinoic acid or cisplatin in human ovarian carcinoma cell lines. 962 33

We investigated the intracellular mechanisms of retinoic acid (9-cis-RA, 13-cis-RA or all-trans-RA) and a cyclic AMP analog 8-Cl-cAMP on growth-inhibition and apoptosis in human ovarian cancer NIH: OVCAR-3 and OVCAR-8 cells. The cyclic AMP analog, 8-Cl-cAMP, acted synergistically with RA in inducing and activating retinoic acid receptor beta (RARbeta) which correlated with the growth inhibition, cell cycle arrest, and apoptosis in both cell types. In addition, combined treatment of cells with RA plus 8-Cl-cAMP resulted in the release of cytochrome c, loss in mitochondrial membrane potential and activation of caspase-3 followed by cleavage of anti-poly(ADP-ribose)polymerase and DNA-dependent protein kinase (catalytic subunit). Interestingly, inhibition of caspase-3 activation blocked RA plus 8-Cl-cAMP induced apoptosis. Furthermore, mutations in a CRE-related motif within the RARbeta promoter resulted in loss of both transcriptional activation of RARbeta and synergy between RA and 8-Cl-cAMP. Thus, RARbeta can mediate RA and/or cyclic AMP action in ovarian cancer cells by promoting apoptosis. Loss of RARbeta expression, therefore, may contribute to the tumorigenicity of human ovarian cancer cells. These findings suggest that RA and 8-Cl-cAMP act in a synergistic fashion in inducing apoptosis via caspase-3 activation, and may have potential for combination biotherapy for the treatment of malignant disease such as ovarian cancer.
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PMID:Synergistic effects of retinoic acid and 8-Cl-cAMP on apoptosis require caspase-3 activation in human ovarian cancer cells. 1020 36

Both cAMP and retinoids play a role in cell differentiation and the control of cell growth. A site-selective cAMP analog, 8-Cl-cAMP and retinoic acid synergistically inhibit growth and induce apoptosis in certain cancer cells. In advanced or recurrent malignant diseases, retinoic acid (RA) is not effective even at doses that are toxic to the host. The objective of our present study was to examine the mechanism(s) of synergistic effects of retinoic acid (9-cis, 13-cis or all-trans RA) and 8-Cl-cAMP on apoptosis in human ovarian cancer NIH: OVCAR-3 and OVCAR-8 cells. RA induced growth inhibition and apoptosis in OVCAR-3 and OVCAR-8 cells. 8-Cl-cAMP acted synergistically with RA in inducing and activating retinoic acid receptor beta (RARbeta) which correlates with growth inhibition and apoptosis in both cell types. In addition, induction of apoptosis by RA plus 8-Cl-cAMP requires caspase-3 activation followed by cleavage of anti-poly(ADP-ribose) polymerase. Furthermore, mutations in CRE-related motif within the RARbeta promoter resulted in loss of both transcriptional activation of RARbeta and synergy between RA and 8-Cl-cAMP. RARbeta expression appears to be associated with induction of apoptosis. Introduction of the RARbeta gene into OVCAR-3 cells resulted in gain of RA sensitivity. Loss of RARbeta expression, therefore, may contribute to the tumorigenicity of human ovarian cancer cells. Thus, combined treatment with RA and 8-Cl-cAMP may provide an effective means for inducing RARbeta expression leading to apoptosis in ovarian cancer cells.
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PMID:Synergistic effects of 8-Cl-cAMP and retinoic acids in the inhibition of growth and induction of apoptosis in ovarian cancer cells: induction of retinoic acid receptor beta. 1071 18

Retinoid derivatives have been implicated for the growth regulation of ovarian cancer cells. However, the molecular mechanisms are not yet fully defined. To dissect detailed mechanisms of each derivative, four ovarian cancer cells (A2774, PA-1, OVCAR-3, SKOV-3) were treated with all-trans retinoic acid (ATRA), 9-cis retinoic acid (9-cis RA), 13-cis RA, or 4-hydroxyphenyl retinamide (4-HPR). When treated with 1 microm, HPR inhibits most effectively the growth of all four cells. Depending on cell types treated, IC(50) values were 0.7-2.7 microm for 4-HPR, and 2.7-9.0 microm for other retinoid derivatives. DNA fragmentation assay indicated that the antiproliferative effect of HPR could be mediated by apoptosis. Transcription assays coupled with transient transfection in OVCAR-3 cells indicated that ATRA, 9-cis RA, and 13-cis RA were active for all RAR/RXR subtypes, whereas 4-HPR was only active for RARgamma. However, 4-HPR exerted the strongest suppression on AP-1 (c-Jun) activity. As expected from AP-1 data, in vitro invasion assays showed that HPR blocked effectively the migration of OVCAR-3 cells. Thus, 4-HPR showed not only more potent antiproliferative activity than any other retinoid derivatives used, but also effectively inhibited the invasion, probably through the suppression of AP-1 activity. Taken together coupled with its selective activity only for RARgamma, these results suggest that 4-HPR could be less toxic, and very effective anticancer drugs for late stage ovarian cancer.
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PMID:Antiproliferative mechanism of retinoid derivatives in ovarian cancer cells. 1168 87

We analyzed the clinicobiological features and treatment outcome of a series of acute promyelocytic leukemias (APLs) occurring as a second tumor (APL-st's, n = 51) and compared these with a large group of de novo APL cases (n = 641), both observed by the Italian cooperative group GIMEMA. In the APL-st group, 37 patients had received radiotherapy and/or chemotherapy for their primary malignancy (PM), while 14 had been treated by surgery alone. Compared with de novo APL patients, APL-st patients were characterized by a predominance of females (P <.003), higher median age (P <.05), and worse performance status (P <.005). The median time elapsed between PM and APL-st was 36 months, with a longer latency for patients treated with surgery alone. No significant differences were found with regard to karyotypic lesions or type of promyelocytic leukemia/retinoic acid receptor alpha (PML/RARalpha) fusion in the 2 cohorts. A high prevalence of PMs of the reproductive system was observed among the female APL-st population (24 [71%] of 34 patients in this group had suffered from breast, uterine, or ovarian cancer). Thirty-one APL-st and 641 de novo APL patients received homogeneous APL therapy according to the all-trans retinoic acid (ATRA) and idarubicin regimen (the AIDA regimen). The complete remission (CR), 4-year event-free survival (EFS), and 4-year overall survival (OS) rates were 97% and 93%, 65% and 68%, and 85% and 78% in the APL-st and de novo APL groups, respectively. In spite of important clinical differences (older age and poorer performance status), the APL-st group responded as well as the de novo APL group to upfront ATRA plus chemotherapy, probably reflecting genetic similarity.
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PMID:Clinicobiological features and outcome of acute promyelocytic leukemia occurring as a second tumor: the GIMEMA experience. 1220 Mar 54


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