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

An acid protease was isolated from the ascitic fluid of a patient with ovarian cancer. It was purified about 400-fold to homogeneity by ammonium sulfate fractionation, gel filtration on Sephadex G-200 and DEAE-cellulose column chromatography. Its molecular weight was calculated to be 28 000 by gel filtration, and its isoelectric points was found to be pH 4.1. It showed similar activities on acid-denatured bovine serum albumin and on acid-denatured bovine hemoglobin, and its optimal pH for both substrates was 3.0. Sulfhydryl compounds and metal ions had no apparent effects on this enzyme, but pepstatin was strongly inhibitory.
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PMID:Purification and properties of an acid protease from human ascitic fluid. 62 87

The development of stable immunoconjugates by the advent of macrocyclic metal chelating agents (DOTA) has enabled us to study the ability of 111In-DOTA-labeled monoclonal antibodies to detect tumor lesions in a pilot radioimmunolocalization study, as well as to evaluate the kinetics, toxicity, and efficacy of i.p. administered 90Y-DOTA-labeled murine monoclonal antibody in a Phase I/II clinical trial of advanced ovarian cancer. The development of serum sickness-like reactions in three of six treated patients, in the absence of previous monoclonal antibody administration, led us to study the potential immunogenicity of the new chelate. Six patients with ovarian cancer received 25 mg of HMFG1 monoclonal antibody coupled with 90Y-DOTA (doses of radioactivity, 15 to 25 mCi), administered i.p. Eight patients with various malignant tumors received low doses (220 micrograms to 1 mg) of monoclonal antibodies, labeled with 111In-DOTA, i.v. for imaging studies. Using a solid-phase enzyme-linked immunosorbent assay method, the immunogenicity of DOTA was evaluated. Serial dilutions of patients' sera, before and after imaging or therapy with DOTA-coupled monoclonal antibodies, as well as sera from patients who did not receive DOTA-coupled antibody, were screened on enzyme-linked immunosorbent assay plates coated with human serum albumin (HSA), HSA-2-iminothiolane, and HSA-2-iminothiolane-benzyl-DOTA. All patients treated with i.p. monoclonal antibody developed anti-DOTA antibodies. Four of eight patients who received i.v. "imaging" doses of DOTA-coupled monoclonal antibody developed antibodies against DOTA. The levels of anti-DOTA response correlated with the amount of injected radioimmunoconjugate (r = 0.889, P less than 0.001). None of the patients who received DOTA-coupled antibody had detectable antibodies against the macrocycle before immunoconjugate administration. We then addressed further the restriction of the immune response against the macrocycle. We found that there was no or very low response against the aromatic ring attached to DOTA. Most, if not all, of the immune response is directed against the DOTA ring structure. Affinity purification of anti-DOTA antibody from serum enabled quantitation of these antibodies in the serum of patients. An inverse, statistically significant correlation was observed between the percentage of binding inhibition of a patient's serum to DOTA, by HSA-2-iminothiolane-DOTA (100 micrograms/ml) and the level of anti-DOTA immunoglobulin in the serum.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Development of humoral immune responses against a macrocyclic chelating agent (DOTA) in cancer patients receiving radioimmunoconjugates for imaging and therapy. 173 53

Ricin A chain immunotoxin constructed with monoclonal antibody 791T/36, which recognizes a tumor associated glycoprotein Mr 72,000 antigen present on sarcomas and colon and ovarian cancer cells, is cytotoxic for cell lines from tumors expressing this antigen. Incubation of sarcoma 791T cells with immunotoxin for only 5 min is sufficient to produce greater than 95% inhibition of tumor cell growth. Papain treatment of these cells to remove immunotoxin from the cell surface indicated that the cell surface acts as a reservoir for continued internalization of immunotoxin over several hours, but even so, 50% inhibition of cell survival was produced over a 2- to 3-h period. Analysis of the rate of endocytosis demonstrated that 30-50% of cell bound immunotoxin was internalized over a 180-min period. This was primarily dictated by the antibody moiety, regardless of the degree of conjugation to ricin A chain. This rate is much slower than that of other cell surface ligands such as transferrin. Cell cytosol acidification experiments were performed to determine whether this immunotoxin was internalized by clathrin coated pits, which is relatively rapid, or by smooth pits, which is slower, and the results indicated the latter mechanism is almost exclusively used. Intracellular trafficking of antibody 791T/36, conjugated to human serum albumin-tetramethylrhodamine was investigated by flow cytometry. The movement of the conjugate into the lysosomal compartment was delayed so that degradation products were only detected after a lag phase of 30-60 min. The lack of potentiator dependence of 791T/36 immunotoxin is in keeping with these findings.
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PMID:Endocytosis of immunotoxin-791T/36-RTA by tumor cells in relation to its cytotoxic action. 200 18

The CA 125 antigenic determinant has been shown to be elevated in the serum of ovarian cancer patients and is a useful prognostic marker. The chemical epitope which characterizes the CA 125 antigen is found on a high molecular weight glycoprotein and has been suggested to be carbohydrate in nature. This study was undertaken to establish the relationship of a carbohydrate to the epitope recognized by the monoclonal antibody, OC 125. Along this line a carbohydrate structure conjugated to bovine serum albumin (BSA), was enzymatically sialylated using a purified sialyltransferase to yield NeuAcGal[GlcNAc]GalNAc-OC6H4N = N-BSA. This sialylated product was used to immunize a goat and two rabbits for the development of polyclonal antisera. The resultant antisera were tested against related carbohydrates in EIA biased competitive inhibition assays. It was determined that the GlcNAc(beta 1-6)GalNAc residue was immunologically dominant for all antisera tested. As the immune response matured (greater than 40 days), there was an increase in the proportion of the antibodies that were directed to the NeuAc(alpha 2-3)Gal(beta 1-3)GalNAc residue compared to the nonsialylated form. Known CA 125 molecules did not inhibit the binding of raised antisera to the sialylated product, nor did the sialylated product react with OC 125 monoclonal antibodies. It was therefore concluded that the carbohydrate structure in question is not the epitope, or is not a large enough part of the epitope to be recognized in these assays by the OC 125 monoclonal antibodies.
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PMID:Antigenic studies on an enzymatically sialylated carbohydrate: NeuAc(alpha 2-3)Gal(beta 1-3)[GlcNAc(beta 1-6)]GalNAc. 205 2

Daunorubicin (DNR) or doxorubicin (DOX) was modified with one of four "linker reagents" to produce electrophilic drug analogues for synthesis of bioconjugates. Synthesis and characterization of two new reagents [p-isothiocyanatobenzoyl chloride and 3-(p-isothiocyanatophenyl) propionyl chloride] are described here for the first time. Adding one of the new reagents, bromoacetyl bromide, or p-(fluorosulfonyl)-benzoyl chloride in chloroform to an alkaline aqueous solution of DNR (or DOX) provided excellent yields of the corresponding, electrophilic 3'-N-amide analogue. The DNR and DOX analogues were characterized by thin-layer chromatography, nuclear magnetic resonance spectroscopy, and infrared spectroscopy. Bioconjugates were produced with the electrophilic DNR or DOX analogues by mixing them with bovine serum albumin (BSA), mouse IgG, or a monoclonal antibody (OC125, which specifically binds to the CA125 antigen from human ovarian carcinoma). The relative reactivity of the 3'-N-substituents toward protein is p-(fluorosulfonyl)benzoyl greater than phenylisothiocyanato greater than bromoacetyl. Overall, the new phenyl isothiocyanate acid chlorides are superior to p-(fluorosulfonyl)benzoyl chloride or bromoacetyl bromide as reagents with which to produce electrophilic DNR or DOX analogues for conjugation with monoclonal antibodies. The bioconjugates DNR-OC125 and DOX-OC125 are selectively toxic to two human ovarian cancer cell lines in vitro (1) and bind with high specificity to human ovarian tumor sections (2) that express the CA125 antigen.
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PMID:Electrophilic analogues of daunorubicin and doxorubicin. 209 17

The present study was designed to test the in vitro efficacy for human ovarian cancer cells of daunorubicin (DNR) conjugated to a monoclonal antibody (OC125). The OC125 antibody specifically binds to the antigenic protein CA125 from human ovarian carcinoma. New analogs of DNR containing various linker groups were conjugated to mouse monoclonal anti-CA125 antibody (DNR-OC125); nonspecific murine IgG1 (DNR-IgG1); or bovine serum albumin (DNR-BSA). The DNR-protein conjugates were all stable for several days in neutral solutions at room temperature. The DNR-OC125 conjugates selectively killed dividing cell populations but not nondividing cell populations of two human ovarian cancer cell lines (SK-OV-3 or OVCAR-3) that express the CA125 antigen. Equivalent concentrations of DNR-IgG1 or DNR-BSA conjugates were neither toxic to the dividing nor the nondividing populations of SK-OV-3 or OVCAR-3 cells. Only those DNR-protein conjugates linked to OC125 were cytotoxic to dividing cell populations of both cell lines. This indicates that cytotoxicity is dependent on OC125 antibody-CA125 antigen binding which concentrates DNR on the ovarian cancer cells. We advance the hypothesis that following antibody-antigen binding, DNR is released from the conjugate and it intercalates in DNA by a mechanism similar to that of the unmodified DNR. The new DNR-OC125 conjugate may be useful for delivering DNR to ovarian tumors that express the CA125 antigen because the drug-antibody conjugates (1) retain the cytotoxic characteristics of the unmodified drug: (2) specifically kill the human ovarian cancer cells that express the CA125 antigen; and (3) are completely stable for days in neutral solutions at room temperature.
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PMID:Daunorubicin conjugated to a monoclonal anti-CA125 antibody selectively kills human ovarian cancer cells. 278 1

Intestinal obstruction is frequently encountered in patients with ovarian cancer. Surgical correction of intestinal obstruction may allow the prolonged survival of some patients. We identified prognostic factors associated with operative complications and postoperative survival. Multiple preoperative, intraoperative, and postoperative variables were considered. In addition, a previously published prognostic index was evaluated. Statistical assessment developed a model that demonstrated that the clinical assessment of tumor status, the serum albumin level, and the nutrition score were variables significantly associated with postoperative survival. The amount of residual ovarian cancer at the completion of bowel obstruction surgery was also significantly associated with postoperative survival. This information may aid in the preoperative selection of patients who might benefit from surgical correction of intestinal obstruction.
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PMID:Intestinal obstruction in patients with ovarian cancer. Variables associated with surgical complications and survival. 333 55

Patients with concomitant ovarian cancer and bowel obstruction were studied in an effort to find objective prognostic factors predictive of patient outcome. A total of 62 patients were followed from 31 to 354 weeks, and a total of 20 variables were considered in the analyses. At the end of the study 49 patients were dead of their disease, and 13 were alive (six disease free and seven with persistent disease). Survival probabilities of the sample were 79% at 6 weeks, 48% at 20 weeks, and 24% at 104 weeks. Univariate analyses revealed no significant difference in the survival times of medically versus surgically treated patients; age greater than 60 years at diagnosis of cancer, presence of ascites, low serum albumin levels, elevated blood urea nitrogen levels, elevated alkaline phosphatase levels, lack of previous radiotherapy (p less than 0.002 for all), advanced tumor stage, normal/ileus x-ray results, and a short diagnosis to obstruction interval (p less than 0.04 for all) resulted in lower survival probabilities.
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PMID:Bowel obstruction in patients with ovarian cancer: a search for prognostic factors. 334 1

We studied the factors that control the capacity of tumor cells to grow in soft agar. And, we analyzed the effect of cell-free ascites (CFA) obtained from ovarian cancer patients in combination with various media on the cloning efficiency of H-134 and OVCAR-3nu ovarian carcinoma cell lines and the WiDr colon carcinoma cell line. Seven batches of CFA consistently enhanced the soft agar growth of tumor cells more efficiently than tested sera. The addition of charcoal-treated bovine serum albumin (BSA) lowered the amount of CFA required for optimal tumor cell growth. As little as 1.25 ng of epidermal growth factor (EGF)/ml further improved OVCAR-3nu soft agar growth in combination with all of the amounts of CFA tested. Thus, neither BSA nor EGF seems to account for the colony-stimulating effect of ascites on tumor cells. Four batches of CFA were tested for stimulating soft agar growth of normal rat kidney (NRK-49F) fibroblasts; all induced colonies of different morphologies. This effect was potentiated by EGF, which suggests the presence of several transforming growth factor-like activities in CFA. The results show that differences in cloning efficiency of tumor cells of one or two orders of magnitude can be found between standard (anchorage-dependent growth-supporting) media and media optimalized for soft agar growth, such as CFA in the presence of EGF. This paper will discuss the similarity in effects of CFA on various tumor cells and NRK cells, and possible implications of the stimulatory effects of CFA.
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PMID:Analysis of human ascites effect on clonogenic growth of human tumor cell lines and NRK-49F cells in soft agar. 357 52

In human tumor cells freshly obtained from patients with breast cancer, ovarian cancer, or adenocarcinoma of unknown etiology and in normal human bone marrow cells, the cell-to-medium ratio (intracellular/extracellular concentration) in vitro of 5.42 microM melphalan rose rapidly to levels of 6-17 after 35 min at 37 degrees C in Dulbecco's phosphate-buffered saline containing bovine serum albumin and glucose. Only patient C (breast cancer) had received chemotherapy. In all cells studied, L amino acids (1 mM) such as leucine, glutamine, tyrosine, and methionine reduced the cell-to-medium ratio of melphalan at 3 and 35 min. There was a good correlation between the reduction of melphalan transport at 35 min in the heterogeneous nucleated bone marrow cell population by amino acids and their effect on melphalan cytotoxicity in the CFU-C system. Aminoisobutyric acid (A1B), a specific substrate of the A system of amino acid transport, at a concentration between 1 and 50 mM had no significant effect on melphalan uptake at 3 min in any of the human cells studied except those of patient C. At 35 min A1B (10 or 50 mM) significantly reduced the intracellular melphalan concentration in normal bone marrow cells and tumor cells from patients B and C. At 2 mM, 2-aminobicyclo-(2, 2,1)-heptane-2-carboxylic acid (BCH), a specific substrate of the L system of amino acid transport, reduced the cell-to-medium ratio to 70% of control at 3 and 35 min in human bone marrow cells. In tumor cells from patients A, B, D, and F, 2 mM BCH had no significant effect on melphalan uptake at 3 min; it slightly decreased uptake in tumor cells from patient C. At 35 min, 2 mM BCH significantly reduced melphalan transport in tumor cells from patients C and F only. The lack of a BCH-suppressible component to melphalan uptake into human tumor cells freshly obtained from previously untreated patients contrasts with the presence of this component in murine L1210 leukemia cells, murine P388 leukemia cells, and human tumor cell lines. This suggests that minor differences in melphalan transport may exist amongst species and also between human tumor cells which are freshly obtained and cell lines maintained in culture.
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PMID:Effects of amino acids on the transport and cytotoxicity of melphalan by human bone marrow cells and human tumor cells. 401 61


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