Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Abnormal FHIT gene expression has been reported in a variety of epithelial tumors shown to harbor deletions of chromosome 3p14, the chromosomal assignment of this gene. Recently, we described loss of heterozygosity of 3p in a subset of epithelial ovarian cancers. To investigate a potential role of the FHIT gene in ovarian cancer, we examined primary cell cultures derived from normal ovarian surface epithelium, ovarian tumors, and the cellular fraction of malignant ascites to determine the expression of FHIT by using reverse transcription-polymerase chain reaction. Included in this analysis were four spontaneously immortalized cell lines: three derived from malignant epithelial ovarian tumors (TOV21G, TOV112D, and TOV81D) and one from malignant ovarian ascites (OV90). OV90 was previously shown to harbor a deletion of the whole p arm of chromosome 3. The FHIT transcript was not detectable in two of 11 primary cultures derived from normal ovarian surface epithelium or in a primary culture derived from malignant ovarian ascites, whereas the remaining samples (34 malignant, eight borderline, and three benign specimens), exhibited identical expression patterns. In each case, this pattern was consistent with the co-expression of a normal FHIT transcript and a smaller transcript. DNA sequencing revealed that the abnormal-sized message lacked exons 4-7 (inclusive), which were deleted at their exact intron-exon splice sites. The aberrant-sized transcript was detectable by Northern blot analysis. There was no concordance between FHIT expression and loss of heterozygosity at the FHIT locus. Northern blot analysis also revealed that FHIT was differentially expressed, and the spontaneously immortalized cell lines TOV21G and TOV112D showed the highest level of expression. Because the same reverse transcription-polymerase chain reaction expression pattern was observed in both normal and tumor-derived primary cell cultures, these results argue against a significant role for FHIT in epithelial ovarian tumorigenesis.
Mol Carcinog 1999 Mar
PMID:Expression of FHIT in primary cultures of human epithelial ovarian tumors and malignant ovarian ascites. 1020 6

ERCC-1 is an essential gene in the nucleotide excision repair pathway, and may be essential for life. However, the mechanism of transcriptional activation and regulation of ERCC-1 gene expression is unclear. We therefore investigated the effect of the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on the expression of the ERCC-1 gene in A2780/CP70 human ovarian carcinoma cells. TPA induced a four- to sixfold increase in steady-state ERCC-1 messenger RNA (mRNA) levels that was time- and concentration-dependent. Nuclear run-on experiments demonstrated that the rate of transcription of ERCC-1 was approximately 2.8-fold higher in TPA-treated cells than in the controls. TPA stimulation of A2780/CP70 cells also resulted in a rapid but transient induction of c-jun and c-fos as determined by Northern and Western blot analyses, which peaked about 2 h before the peak in ERCC-1 expression. Electrophoretic mobility shift assays of nuclear extracts from TPA-treated cells revealed an increase in DNA-binding activity specific for the AP-1-like binding site in the 5'-flanking region of ERCC-1. c-Jun and c-Fos proteins were confirmed to be the components of the activated AP-1 complex by supershift analysis. The increase in AP-1 activity occurs immediately before the increase in ERCC-1 transcription. The increase in AP-1 DNA-binding activity and the increase in ERCC-1 mRNA expression were prevented by pretreatment with cycloheximide. These data suggest that AP-1 may contribute to the upregulation of ERCC-1 in response to TPA in human ovarian cancer cells.
Cell Mol Life Sci 1999 Mar
PMID:Phorbol ester exposure activates an AP-1-mediated increase in ERCC-1 messenger RNA expression in human ovarian tumor cells. 1022 59

Ovarian cancer is the leading cause of death from gynecologic maligancy among women in the United States. In 1997, there were nearly 27,000 ovarian cancer cases with over 14,000 deaths. Recent attempts at early detection of ovarian cancer have been aimed at the identification of biomarkers that would indicate an underlining malignant process or reflect the biological behavior of the tumor. Our previous studies revealed that chromosome 8 copy number abnormality, especially trisomy, is common in several cancers. Archival tissues from 24 cases of papillary serous ovarian carcinoma (10 stage I and 14 stage III) were analyzed by fluorescence in situ hybridization (FISH) with a chromosome 8-specific alpha-satellite probe (Oncor, Gaithersburg, MD). The analysis was done according to standard protocols of the Lifespan Academic Medical Center Cytogenetics Laboratory at Rhode Island Hospital. Twenty-one of 24 cases (87.5%) were found to be trisomic for chromosome 8, if a cutoff point of >/=15% cells with three signals is adopted. Overall, 80% of stage I and 93% of stage III tumors had trisomy 8. This study confirms the presence of a high frequency of trisomy 8 in both early and late stages of the disease and suggests that trisomy 8 may be an early event in the multistep process leading to ovarian cancer. It is of interest to note that a higher frequency of trisomy 8 was found in a higher stage of disease, consistent with our previous results on breast cancer. Thus, additional FISH studies of ovarian tumors for chromosome 8 copy number assessment may be warranted.
Exp Mol Pathol 1999 Apr
PMID:Trisomy 8 in stage I and stage III ovarian cancer detected by fluorescence in situ hybridization. 1033 67

The role of FSH in gonadal tumorigenesis and, in particular, in human ovarian cancer has been debated. It is also unclear what role the elevated FSH levels in the inhibin-deficient mouse play in the gonadal tumorigenesis. To directly assess the role of FSH in gonadal growth, differentiation, and gonadal tumorigenesis, we have generated both gain-of-function and loss-of-function transgenic mutant mice. In the gain-of-function model, we have generated transgenic mice that ectopically overexpress human FSH from multiple tissues using a mouse metallothionein-1 promoter, achieving levels far exceeding those seen in postmenopausal women. Male transgenic mice are infertile despite normal testicular development and demonstrate enlarged seminal vesicles secondary to elevated serum testosterone levels. Female transgenic mice develop highly hemorrhagic and cystic ovaries, have elevated serum estradiol and progesterone levels, and are infertile, mimicking the features of human ovarian hyperstimulation and polycystic ovarian syndromes. Furthermore, the female transgenic mice develop enlarged and cystic kidneys and die between 6-13 weeks as a result of urinary bladder obstruction. In a complementary loss-of-function approach, we have generated double-homozygous mutant mice that lack both inhibin and FSH by a genetic intercross. In contrast to male mice lacking inhibin alone, 95% of which die of a cancer cachexia-like syndrome by 12 weeks of age, only 30% of the double-mutant male mice lacking both FSH and inhibin die by 1 yr of age. The remaining double-mutant male mice develop slow-growing and less hemorrhagic testicular tumors, which are noted after 12 weeks of age, and have minimal cachexia. Similarly, the double-mutant female mice develop slow-growing, less hemorrhagic ovarian tumors, and 70% of these mice live beyond 17 weeks. The double-mutant mice demonstrate minimal cachexia in contrast to female mice lacking only inhibin, which develop highly hemorrhagic ovarian tumors, leading to cachexia and death by 17 weeks of age in 95% of the cases. The milder cachexia-like symptoms of the inhibin and FSH double-mutant mice are correlated with low levels of serum estradiol and activin A and reduced levels of aromatase mRNA in the gonadal tumors. Based on these and our previous genetic analyses, we conclude that elevated FSH levels do not directly cause gonadal tumors. However, these results suggest FSH is an important trophic modifier factor for gonadal tumorigenesis in inhibin-deficient mice.
Mol Endocrinol 1999 Jun
PMID:Transgenic models to study gonadotropin function: the role of follicle-stimulating hormone in gonadal growth and tumorigenesis. 1037 85

Forty tumor specimens from patients with ovarian cancer were studied for amplification of the c-myc oncogene relative to chromosome 8 centromere number using dual-color FISH. Interphase cytogenetic analysis showed amplification of the c-myc oncogene in 40% (16/40) of tumors using the standard oncogene:centromere ratio method of analysis. Eleven of these showed moderate amplification of c-myc, and 5 samples showed high amplification. Eight of the sixteen (50%) amplified tumors were polysomic centromere 8 as were 14 of the 24 (58%) non-amplified tumors. In previously reported work with these samples, the oncogene HER-2/neu, the chromosome 17 centromere, and the tumor suppressor gene p53 had been studied. When using the standard oncogene:centromere ratio criteria, 5 samples had amplification of both the c-myc and the HER-2/neu oncogenes, 5 samples had HER-2/neu amplification but not c-myc, 11 samples had c-myc amplification but not HER-2/neu, and 19 samples had neither oncogene amplified. The p53 gene was found to be deleted in 22.5% (9/40) of samples. The loss of the p53 gene did not appear to have any clinical correlation. The presence of an extra centromere 8 also did not appear to have any clinical correlation. The Kaplan-Meier survival curve for those patients who have c-myc amplification, while not statistically significant, appears to show a trend toward poorer survival. The survival curve for patients whose tumors have HER-2/neu amplification shows no clinical significance. It is of great interest, however, that the Kaplan-Meier plot of survival for patients whose tumors have amplification of both c-myc and HER-2/neu shows a significant difference (P = 0.047). The median survival times of the doubly amplified patient group and the non-doubly amplified groups were 12 and 43 months, respectively. This is the first study of the oncogene c-myc using FISH. The results suggest that the amplification of c-myc may indicate a poorer patient survival and that the amplification of both c-myc and HER-2/neu in combination may be a better prognostic indicator of poor patient survival.
Exp Mol Pathol 1999 Jun
PMID:c-myc and chromosome 8 centromere studies of ovarian cancer by interphase FISH. 1040 42

BRCA1 mutation research in ovarian and breast cancer 17q21-linked families has yielded a large number of germline sequence variations. Somatic mutations have been uncommonly reported. We screened 81 probands with primary ovarian, peritoneal, or fallopian tube carcinoma for BRCA1 mutations. The study group was intentionally biased by the inclusion of 29 probands with a family history of ovarian and/or breast carcinoma, 13 probands diagnosed on or before age 45, seven individuals with a metachronous breast cancer and 51 tumors with BRCA1 LOH. Tumor and/or germline DNA was screened by modified techniques of single-strand confirmation polymorphism analysis, and abnormal banding patterns were sequenced to confirm mutations. Twenty-one (25.9%) BRCA1 sequence variations were identified. Eight mutations were somatic including seven null mutations. Apart from classical hereditary ovarian/breast cancer, a family history of ovarian/breast cancer defines a subset of ovarian cancer individuals with a significant likelihood of either a germline or a somatic BRCA1 gene sequence variation.
Mol Genet Metab 1999 Aug
PMID:BRCA1 mutations in familial ovarian cancer. 1044 47

Bispecific antibody (bsAb)-based clinical trials of cancer have been conducted primarily using intact murine monoclonal antibody (mAb)-derived molecules. In some of these trials, toxicity resulting from the interactions of antibody Fc domains with cellular Fc receptors has limited the doses of antibody (Ab) that can be employed. Furthermore, human anti-mouse Ab responses prohibit multiple therapy courses. These factors have decreased the efficacy of the bsAb 2B1, which targets the extracellular domains (ECD) of the HER2/neu protooncogene product and the human FcgammaRIII (CD16). To address these obstacles, we have constructed and characterized a fully human gene-fused bsAb from single-chain Fv (scFv) molecules specific for HER2/neu and CD16. The human anti-CD16 scFv component, NM3E2, was isolated from a human scFv phage display library. As binding of NM3E2 to human neutrophil-associated CD16 decreased in the presence of plasma IgG, we have concluded that NM3E2 recognizes an epitope in the vicinity of the Fc binding pocket. Furthermore, the NM3E2 scFv was found by surface plasmon resonance-based epitope mapping to share an overlapping epitope with the Leu-11c mAb. The human anti-HER2/neu scFv component, C6.5, which was previously isolated from a human scFv phage display library, was employed as fusion partner for the creation of a bispecific scFv (bs-scFv). In the presence of the C6.5 x NM3E2 bs-scFv, peripheral blood lymphocytes promoted significant lysis of human SK-OV-3 ovarian cancer cells overexpressing HER2/neu. Biodistribution studies performed in SK-OV-3 tumor-bearing scid mice revealed that 1% ID/g of 125I-labeled C6.5 x NM3E2 bs-scFv was specifically retained in tumor at 23 h following injection. These results indicated that both scFv components of the bs-scFv retained their function in the fusion protein. This bsAb should overcome some of the problems associated with the 2B1 bsAb. C6.5 x NM3E2 bs-scFv offers promise as a platform for multifunctional binding proteins with potential clinical applications as a result of its human origin, lack of an Fc domain, ease of production, high level of in vitro tumor cell cytotoxicity and highly selective tumor targeting.
Mol Immunol 1999 May
PMID:Isolation and characterization of an anti-CD16 single-chain Fv fragment and construction of an anti-HER2/neu/anti-CD16 bispecific scFv that triggers CD16-dependent tumor cytolysis. 1044 96

Interleukin (IL)-3 is a multipotent hematopoietic growth factor produced by activated T cells, monocytes/macrophages and stroma cells. The human IL-3 gene is located on chromosome 5 near segment 5q31. The high-affinity receptor for human IL-3 is composed of alpha and beta subunits. IL-3 shares a common beta subunit with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-5; this subunit has been mapped to chromosome 22q13.1. The biological effects of IL-3 have been studied in human and murine hematopoietic cell lines and normal human marrow cells. Addition of IL-3 to the culture medium induces proliferation, maturation and probably self-renewal of pluripotent hematopoietic stem cells and cells of myeloid, erythroid and megakaryocytic lineages. Human IL-3 was cloned in 1986, and since then various clinical trials have assessed the in vivo potential of recombinant human (rhIL-3). Initial results of phase I/II studies of IL-3 at a dose of 5-10 microg/kg subcutaneously daily for 5-10 days in patients with relapsed lymphomas, small-cell lung cancer, breast cancer and ovarian cancer showed that post-chemotherapy application of IL-3 reduces chemotherapy delays and induces faster regeneration of granulocytes and platelets. However, these results were not confirmed in phase III studies. The role of IL-3 alone in the treatment of myelodysplastic syndromes (MDS), aplastic anemia (AA) and other bone marrow failure disorders have also been disappointing. However, preliminary studies of IL-3 in combination with chemotherapeutic agents and immunosuppression have demonstrated encouraging results in patients with MDS and AA respectively. The therapeutic potential of IL-3 in peripheral blood stem cell (PBSC) harvesting and priming of stem cells before harvest is beginning to be identified. Initial results of IL-3 combination with GM-CSF or later-acting growth factors such as granulocyte colony-stimulating factor (G-CSF) have yielded larger amounts of PBSC during harvesting. In recent years, the availability of synthetic IL-3 receptor (IL-3R) agonists and similar chimeric molecules with greater in vitro biological activity and fewer inflammatory side-effects has extended our options to employ and compare these molecules and rhIL-3 for the prevention of chemotherapy-induced myelosuppression. The role of IL-3 and IL-3R agonists in ex vivo expansion of stem cells, dendritic cell development and gene transfer requires further evaluation. It appears that future application of IL-3 in combination with other cytokines is an attractive way forward in the prevention of treatment-related mortality and morbidity in oncology patients. It also shows prospects for the development of new therapeutic strategies for dose escalation and immune modulation for cancer patients with relapsed and resistant disease.
Cytokines Cell Mol Ther 1999 Jun
PMID:Interleukin-3 in hematology and oncology: current state of knowledge and future directions. 1051 81

The identification of the breast/ovarian susceptibility genes, BRCA1 and BRCA2 was an important advancement in the field of breast and ovarian cancer research. About 40-50% of site specific hereditary breast cancers and up to 80% of hereditary breast-ovarian cancers result from mutations in the BRCA1 gene. Although BRCA1 mediates multiple functions in the cell, including a role in DNA damage repair and gene transcription, the role of BRCA1 has not completely been elucidated yet. It has been suggested that mutational inactivation of TP53 may be required for BRCA1-associated tumorigenesis. Several studies have shown that TP53 is more frequently inactivated in BRCA1-associated tumors than in sporadic breast or ovarian cancer. Up to 90% of BRCA1-associated tumors harbor either a TP53 mutation and/or TP53 protein accumulation. The remaining tumors may well have other alterations affecting the cell cycle checkpoint. Loss of this checkpoint may be obligatory for BRCA1-tumorigenesis. In this review, we discuss recent advances in BRCA1-research and stress the pivotal role TP53 may play in BRCA1-associated carcinogenesis.
Mol Cell Endocrinol 1999 Sep 10
PMID:Is TP53 dysfunction required for BRCA1-associated carcinogenesis? 1058 Aug 47

Wild-type p53 is frequently mutated in late-stage ovarian cancer and has been proposed as a determinant of cisplatin chemosensitivity. We have therefore established a human ovarian cancer cell line differing only in p53 status and characterized its response after treatment with different platinum complexes. The wild-type p53-expressing cell line A2780 was stably transfected with HPV-16 E6 (E6) or an empty vector (VC) as control. Parental A2780 and VC had similar cisplatin sensitivities, whereas E6 was 3- to 4-fold more sensitive as measured by sulforhodamine B and clonogenic assay. E6 was 2- to 3-fold more sensitive to transplatin and the novel cisplatin analog ZD0473 than VC, whereas the trans-platinum analog JM335 was approximately equitoxic. Platinum uptake was similar for all of the cell lines after cisplatin. The removal of platinum-DNA adducts, as measured by atomic absorption spectroscopy, was reduced in E6 compared with VC after cisplatin but similar after JM335. After 10 microM cisplatin, the G(1) population (0-96 h) was reduced in E6 cells compared with VC, whereas the S phase (8-48 h) and G(2) phase (48-96 h) were increased. Similar proportions of VC and E6 cells died by apoptosis, as detected by annexin V binding, but more E6 cells died by necrosis relative to VC. Our results suggest that the loss of functional p53 can increase cisplatin cytotoxicity in A2780, with loss of G(1)/S checkpoint control and decreased cisplatin-DNA adduct repair, but these effects can be circumvented by the use of JM335, which forms different DNA-platinum adducts.
Mol Pharmacol 2000 Mar
PMID:Effect of p53 status on sensitivity to platinum complexes in a human ovarian cancer cell line. 1069 90


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