UMLS:C0026764 - FACTA Search

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Query: UMLS:C0026764 (multiple myeloma)
36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have employed conventional polymerase chain reaction (PCR) and nonpalindromic adaptor PCR (NPA-PCR) for the amplification of the heavy- and light-chain transcripts of the cDNAs of two human monoclonal antibodies (MAb), designated AC6C3 (IgM, lambda) and CR4E8 (IgM, lambda), recognizing two different antigens expressed on the cell surface of human ovarian, cervix, breast, colon, melanoma and other carcinomas. With few exceptions these MAbs do not react with normal tissues. The AC6C3 MAb was developed by fusing regional lymph node lymphocytes from a patient with ovarian carcinoma with cells of the hybrid myeloma line SPAZ4, whereas the CR4E8 MAb was developed by fusing SPAZ4 cells with peripheral blood lymphocytes from a patient with cervical cancer, who was immunized intralymphatically with a viral oncolysate allogeneic tumor vaccine. The AC6C3 MAb immunoprecipitated from lysates of the ovarian tumor cell line SKOV3 a 32 kD polypeptide. The CR4E8 MAb reacted in Western blotting of lysates of the SW756 cervical carcinoma line with a 55 kD band. Cell surface immunofluorescence determinations using the fluorescence activated cell sorter revealed that both MAbs stain ovarian or cervix carcinoma tumor cell lines. We amplified the heavy chain transcripts of these two MAbs by conventional PCR, using mixed 5' end amplification primers, corresponding to the most conserved VH leader sequences and a C mu probe as a 3' end amplification primer. However, the mixed primer approach did not permit the amplification of the lambda-chain transcripts of these two human MAbs. This amplification was successfully carried out using the NPA-PCR that we have previously developed, specifically for the amplification of transcripts with unknown or variable 5' end, such as the T-cell receptors and the immunoglobulins. We have cloned and sequenced the amplified cDNAs. Sequence analysis showed that the V lambda segment of the AC6C3 MAb had 80.29% homology to the human germline Ig lambda-chain V lambda III.1, clone DPL2. The V lambda region of the CR4E8 MAb had 99.28% homology also to the human germline Ig lambda-chain, V lambda III.1, clone DPL23. The AC6C3 MAb lambda-chain employed a J segment with 98% homology to J3. The CR4E8 MAb light chain employed the J(H6-3C4) gene segment. Both MAbs utilized identical VH and JH gene segments and different DH segments. The VH regions of the AC6C3 MAb and of the CR4E8 MAb had, respectively, 98.6% and 98.98% homology to the human Ig germline heavy chain V region DP-7, a member of the VH-1 gene family.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Amplification of immunoglobulin transcripts by the non-palindromic adaptor polymerase chain reaction (NPA-PCR). Nucleotide sequence analysis of two human monoclonal antibodies recognizing two cell surface antigens expressed in ovarian, cervix, breast, colon and other carcinomas. 775 78

The splenocyte of BALB/c mice, immunized with soluble and ovarian serous papillary cystedenoma-associated antigen CA925, was fused with NS-1 myeloma cell strain to produce a monoclonal antibody. 5 cell strains of the monoclonal antibody with continuous secretion were obtained. The fusion openings were used as code names: OC4D9, OC7E10, OC1B4, OC3B8, and OC9B9, their titers were 1: 10(7), 1: 10(7), 1: 10(6), 1: 10(4) and 1: 10(5) respectively. Ig subgroups were IgM and IgG. The chromosomes showed the characteristics of their parents. The 5 strains of the monoclonal antibody obtained presented specific reactions to CA925, no positive reaction with normal ovarian tissues or leiomyoma of the uterus were seen, and there were weak reactions with carcinomas of the lung, the stomach, the kidney, the esophagus and the rectum. Immunohistochemical tests proved that the monoclonal antibody produced was specific against ovarian epithelial carcinoma, and it might offer a means to the diagnosis and treatment of malignant ovarian tumors.
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PMID:[Production and identification of a monoclonal antibody against a tumor associated antigen from ovarian epithelial carcinoma]. 800 14

Intrinsic and acquired multidrug resistance (MDR) in many human cancers may be due to expression of the multidrug transporter P-glycoprotein (Pgp), which is encoded by the mdr1 gene. There is substantial evidence that Pgp is expressed both as an acquired mechanism (e.g., in leukemias, lymphomas, myeloma, and breast and ovarian carcinomas) and constitutively (e.g., in colorectal and renal cancers) and that its expression is of prognostic significance in many types of cancer. Clinical trials of MDR modulation are complicated by the presence of multiple-drug-resistance mechanisms in human cancers, the pharmacokinetic interactions that result from the inhibition of Pgp in normal tissues, and, until recently, the lack of potent and specific inhibitors of Pgp. A large number of clinical trials of reversal of MDR have been undertaken with drugs that are relatively weak inhibitors and produce limiting toxicities at doses below those necessary to inhibit Pgp significantly. The advent of newer drugs such as the cyclosporin PSC 833 (PSC) provides clinicians with more potent and specific inhibitors for MDR modulation trials. Understanding how modulators of Pgp such as PSC 833 affect the toxicity and pharmacokinetics of cytotoxic agents is fundamental for the design of therapeutic trials of MDR modulation. Our studies of combinations of high-dose cyclosporin (CsA) or PSC 833 with etoposide, doxorubicin, or paclitaxel have produced data regarding the role of Pgp in the clinical pharmacology of these agents. Major pharmacokinetic interactions result from the coadministration of CsA or PSC 833 with MDR-related anticancer agents (e.g., doxorubicin, daunorubicin, etoposide, paclitaxel, and vinblastine). These include increases in the plasma area under the curve and half-life and decreases in the clearance of these cytotoxic drugs, consistent with Pgp modulation at the biliary lumen and renal tubule, blocking excretion of drugs into the bile and urine. The biological and medical implications of our studies include the following. First, Pgp is a major organic cation transporter in tissues responsible for the excretion of xenobiotics (both drugs and toxins) by the biliary tract and proximal tubule of the kidney. Our clinical data are supported by recent studies in mdr-gene-knockout mice. Second, modulation of Pgp in tumors is likely to be accompanied by altered Pgp function in normal tissues, with pharmacokinetic interactions manifesting as inhibition of the disposition of MDR-related cytotoxins (which are transport substrates for Pgp). Third, these pharmacokinetic interactions of Pgp modulation are predictable if one defines the pharmacology of the modulating agent and the combination. The interactions lead to increased toxicities such as myelosuppression unless doses are modified to compensate for the altered disposition of MDR-related cytotoxins. Fourth, in serial studies where patients are their own controls and clinical resistance is established, remissions are observed when CsA or PSC 833 is added to therapy, even when doses of the cytotoxin are reduced by as much as 3-fold. This reversal of clinical drug resistance occurs particularly when the tumor cells express the mdr1 gene. Thus, tumor regression can be obtained without apparent increases in normal tissue toxicities. In parallel with these trials, we have recently demonstrated in the laboratory that PSC 833 decreases the mutation rate for resistance to doxorubicin and suppresses activation of mdr1 and the appearance of MDR mutants. These findings suggest that MDR modulation may delay the emergence of clinical drug resistance and support the concept of prevention of drug resistance in the earlier stages of disease and the utilization of time to progression as an important endpoint in clinical trials. Pivotal phase III trials to test these concepts with PSC 833 as an MDR modulator are under way or planned for patients with acute myeloid leukemias, multiple myeloma, and ovarian carcinoma.
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PMID:Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein. 927 28

We have identified three unbalanced translocations involving chromosomes 5 and 17, der(5)t(5;17), der(17)t(5;17), and dic(5;17), in the malignant cells from 17 patients with myeloid neoplasms. Six patients had a primary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) de novo; ten patients had therapy-related MDS and/or AML (t-MDS/t-AML), and one patient had chronic myelogenous leukemia in myeloid blast phase. Two of the six patients with MDS or AML de novo had extensive exposure to industrial solvents, and one patient had Seckel syndrome. The primary diagnoses for the ten patients with t-MDS/t-AML were breast carcinoma and Hodgkin's disease in two patients each, and non-Hodgkin's lymphoma, multiple myeloma, chronic lymphocytic leukemia, ovarian carcinoma, thyroid carcinoma, and rhabdomyosarcoma in one patient each. Four patients had received both prior chemotherapy and radiotherapy, four others received prior chemotherapy only, and the remaining two patients only prior radiotherapy. Fluorescence in situ hybridization of centromere-specific probes for chromosomes 5 and 17 revealed that a dicentric rearrangement was the most common (13/16 patients examined). The genetic consequences of these chromosomal rearrangements are partial monosomy for 5q and 17p. Two of six patients examined had point mutations in TP53, suggesting that loss of function of TP53 in addition to loss of a tumor suppressor gene on 5q may be involved in the pathogenesis of the malignant disease in some of these patients.
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PMID:dic(5;17): a recurring abnormality in malignant myeloid disorders associated with mutations of TP53. 936 36

The bispecific OC/TR monoclonal antibody (mAb) cross-links the CD3 molecule on T cells with the human folate-binding protein (FBP), which is highly expressed on nonmucinous ovarian carcinomas. Clinical trials of patients with ovarian carcinoma with the OC/TR mAb have shown some complete and partial responses. Most patients developed human anti-murine immunoglobulin antibodies (HAMA), which can inhibit OC/TR mAb-mediated lysis. We generated a chimeric version of the OC/TR mAb to decrease the immunogenicity of the OC/TR mAb and to allow more extended treatment schedules. Sp2/0 myeloma cells were transfected with chimeric heavy- and light-chain genes encoding the anti-CD3 mAb and the MOv18 mAb, respectively, which are reactive with FBP. The resulting cell line produced 80 micrograms/ml of total immunoglobulin G (IgG), of which 11.5% was the functionally active chimeric OC/TR mAb. Chimeric OC/TR F(ab')2 fragments mediated lysis of IGROV-1 ovarian carcinoma cells by human T cells at antibody concentrations of > or = 1 pg/ml. Specific lysis was still detectable at an effector-to-target cell ratio as low as 0.4. Two patients with ovarian carcinoma treated with F(ab')2 fragments of the murine OC/TR developed distinct HAMA titers, which were mainly anti-idiotypic and only partly directed against the murine antibody constant regions. However, of the two patients that were treated with the F(ab')2 fragments of the chimeric OC/TR mAb, only one developed a low transient HAMA response just above background level. In conclusion, the generation of chimeric OC/TR may allow more extended clinical studies of bispecific mAb-mediated immunotherapy of ovarian carcinoma.
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PMID:Chimeric bispecific OC/TR monoclonal antibody mediates lysis of tumor cells expressing the folate-binding protein (MOv18) and displays decreased immunogenicity in patients. 940 56

Irradiation of human ovarian carcinoma cells (OVCAR 3) and myeloma cells (RPMI 8226) with graded doses of 137Cs-gamma-rays led to a 35-40% increase in time-dependent apoptosis 72 hr after 6-8 Gy irradiation. Large individual variations in sensitivity to radiation-induced apoptosis were noted in human lymphocytes obtained from 5 donors. Pretreatment of OVCAR 3 and RPMI 8226 cells with 0.01 Gy increased their resistance to apoptosis after subsequent 6 Gy irradiation several hours or 48 and 72 hr later. A dose of 4 or 8 Gy given in 2 equal fractions at an interval of a few hours produced a low level of apoptosis compared to that resulting from a single administration of the same total dose. Adaptive response was demonstrated in 2 out of 3 samples of human lymphocytes isolated from different donors, and no split-dose effect for apoptosis was noted in 2 other donors. In split-dose experiments, there was no correlation between the sensitivity of cells to apoptosis and their position in the cell cycle, after the first half-dose. No G1 block was observed in irradiated cell lines. Adaptive response and split-dose effect were prevented by 3-aminobenzamide and okadaic acid which inhibit poly(ADP-ribose)polymerase and protein phosphatase, respectively. These results imply a common mechanism for acquired resistance to radiation-induced apoptosis in adaptive response and the split-dose effect.
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PMID:Radiation-induced apoptosis in human tumor cell lines: adaptive response and split-dose effect. 963 97

We conducted a population-based study to determine the contribution of germline mutations in known candidate genes to ovarian cancer diagnosed at age <30 years. Women with epithelial ovarian cancer were identified through cancer registries. DNA samples were analyzed for mutations in BRCA1, the "ovarian cancer-cluster region" (nucleotides 3139-7069) of BRCA2, and the mismatch-repair genes hMSH2 and hMLH1. Probable germline mutations in hMLH1 were identified in 2 (2%; 95% confidence interval 1%-8%) of 101 women with invasive ovarian cancer diagnosed at age <30 years. No germline mutations were identified in any of the other genes analyzed. There were no striking pedigrees suggestive of families with either breast/ovarian cancer or hereditary nonpolyposis colorectal cancer (HNPCC). There was a significantly increased incidence of all cancers in first-degree relatives of women with invasive disease (relative risk [RR] = 1.6, P=.01) but not in second-degree relatives or in relatives of women with borderline cases. First-degree relatives of women with invasive disease had increased risks of ovarian cancer (RR = 4.8, P=.03), myeloma (RR = 10, P=.01), and non-Hodgkin lymphoma (RR = 7, P=.004). Germline mutations in BRCA1, BRCA2, msh2, and mlh1 contribute to only a minority of cases of early-onset epithelial ovarian cancer. Our data suggest that early-onset ovarian cancer is not associated with a greatly increased risk of cancer in close relatives.
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PMID:The genetic epidemiology of early-onset epithelial ovarian cancer: a population-based study. 1057 27

Ribavirin, a nucleoside, well known as a broad-spectrum antiviral agent, is extensively used in the treatment of hepatitis C infections. Ribavirin inhibits IMP DH (EC 1.1.1.205) activity and reduces cellular GTP concentration. Quercetin, a plant flavonoid, exhibits antineoplastic activity and inhibits PI 4-kinase (EC 2.7.1.67) and PIP 5-kinase (EC 2.7.1.68) activity. Ribavirin and quercetin attack the cell cycle at the G1 and G1/S boundary, respectively. Because they act on different enzyme targets and arrest the cell cycle at different phases, we tested the hypothesis that ribavirin and quercetin might be synergistic in growth inhibition and cytotoxicity. Human myeloma 8226 and human ovarian carcinoma OVCAR-5 cells were studied because in these cells IMP DH activity increased 14- and 20-fold, respectively, and PI 4- and PIP 5-kinase activities were also elevated. In growth inhibition for ribavirin and quercetin in myeloma 8,226 cells IC50s were 40 and 70 microM, respectively. In OVCAR-5 cells in growth inhibition and clonogenic assays for ribavirin IC50 and LC50 of 35 and 23 microM, respectively, were observed. When quercetin was added 24 h after ribavirin, synergistic antiproliferative action was observed in both myeloma 8,226 and OVCAR-5 cells. Synergistic action was also obtained in OVCAR-5 cells in clonogenic assay when ribavirin was combined with quercetin in the sequence described above. The mechanism of action is provided, in part at least, by the synergistic reduction of signal transduction (IP3 concentration) by ribavirin and quercetin. Ribavirin and quercetin in combination might be of interest in the treatment of myeloma and ovarian carcinoma.
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PMID:Ribavirin and quercetin synergistically downregulate signal transduction and are cytotoxic in human ovarian carcinoma cells. 1060 19

Melphalan was investigated for antitumoral activity using two schedules of exposure (solid versus sequential exposure) in two human cancer cell lines (8226 and A2780). Sequential exposure of melphalan was more effective than solid exposure at the same total dose. The IC50 values averaged 8.2 (solid exposure) and 0.16 microgram/ml (sequential exposure) for 8226 cells (myeloma), and 7.5 (solid) and 0.53 microgram/ml (sequential) for A2780 cells (ovarian carcinoma). Intracellular melphalan accumulation, determined by high-performance liquid chromatography, showed that the area under the intracellular concentration of melphalan versus time curve (between 0 and 30 h) was significantly higher after sequential doses (9.4 micrograms/ml x h) than after solid dose (6.6 micrograms/ml x h). Moreover, intracellular/extracellular concentration ratios indicated that melphalan uptake followed a passive transport system. The increase of both duration of exposure (11 h after solid exposure versus 20 h after sequential doses) and intracellular concentrations 5-6 h after the beginning of the experiment (approximately 3 times higher after sequential doses) indicate sequential administration of melphalan could be more effective than solid exposure.
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PMID:Influence of the schedule of exposure on the cytotoxic effect of melphalan on human 8226 and A2780 cells. 1065 34

Topotecan, a soluble semisynthetic derivative of camptothecin, is a specific inhibitor of topoisomerase I and is endowed of potent antiproliferative effect in vitro and in vivo on tumoral cell lines as well as on endothelial cells. Moreover, topotecan is able to interfere with the development of blood vessels in many in vivo experimental models. During the last years, several phase I clinical studies have demonstrated that the five-daily schedule is the most effective for the treatment of neoplastic diseases of children and adults. In particular, the best clinical results have been obtained in patients affected by metastatic ovarian cancer, small cell (SCLC) and non-small cell lung carcinoma (NSCLC), as well as mammary and gastrointestinal neoplasms. High response rates have been observed in myelodysplastic syndromes and myeloma. The clinical effectiveness of topotecan has been also demonstrated in ovarian carcinoma, even after failure of first or second line chemotherapy and in SCLC, where the response rate is 39%, while the percentage decreases up to 7% in case of drug resistance, with a median survival of 5.4 months. Toxicologic profile of topotecan is foreseeable and manageable, and the most frequent and severe toxicity is represented by myelosuppression. Leukopenia and neutropenia, which follow the administration of topotecan, are non-cumulative and self-limiting and unfrequently complicated by infections, whereas non-hematologic toxicities are uncommon and generally of mild-to-moderate degree. Topotecan is under continuous clinical evaluation for the treatment of neoplasms other than those reported above, alone or in combination with antineoplastic drugs in poly-chemotherapeutic protocols.
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PMID:[Preclinical pharmacology and clinical uses of topotecan]. 1078 94

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