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Biomedical subjects

R Pirker

Publications and source records attributed to R Pirker.

72 records · Page 4Linked to original sources
PubMed1988

Immunotoxins against solid tumors.

Antibody-toxin conjugates, termed immunotoxins, are currently being evaluated as potential new anticancer agents. The monoclonal antibodies that recognize antigens on the surface of tumor cells should deliver the toxins or the catalytic subunits of toxins to cancer cells. The catalytically active parts of the immunotoxins have to reach the cell cytoplasm where they inhibit protein synthesis. Immunotoxins against various solid tumors, including breast carcinoma and ovarian carcinoma, have been developed. In vitro, the activity of immunotoxins is affected by the number of target antigens on the cell surface, the internalization of the immunotoxins, the kind of toxin, the class of the antibody, the kind of linkage, and by other factors. Several problems arise with in vivo administration of immunotoxins. The short serum half-life of immunotoxins, due to their rapid hepatic uptake, decreases the number of immunotoxin molecules that reach the solid tumor. This, together with low tumor penetration by immunotoxins, could lead to low anti-tumor activity. Heterogeneity of tumors, immunogenicity of immunotoxins, and cross-reactivity of immunotoxins with normal tissues are other factors that might limit the clinical use of immunotoxins. It should be possible, however, to overcome these problems using methods that are already available or have yet to be developed.

Antibodies, Monoclonal↗
PubMed1986

B-immunoblastic lymphoma arising in angioimmunoblastic lymphadenopathy.

We present a female patient with a B-immunoblastic lymphoma of the IgM-lambda type arising in angioimmunoblastic lymphadenopathy. An increased ratio of helper/inducer to suppressor/cytotoxic lymphocytes in the lymph node could have triggered the proliferation of B cells. Evolution of IgM cryoglobulinemia was paralleled by malignant transformation in the lymph node. A short-term in vitro chemosensitivity test could predict response to COP combination chemotherapy suggesting that in vitro chemosensitivity testing can be useful for the therapeutic management of angioimmunoblastic lymphadenopathy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

Characterization of immunotoxins active against ovarian cancer cell lines.

The purpose of the present study was to develop immunotoxins directed against human ovarian carcinoma cells. Four monoclonal antibodies (260F9, 454C11, 280D11, and 245E7) were chosen because they were found to bind to various ovarian carcinoma cell lines. These antibodies were covalently linked to either Pseudomonas exotoxin (PE) or ricin A chain (RTA), and the conjugates were tested against five ovarian cancer cell lines (OVCAR-2, -3, -4, -5; A1847). The ability of the immunotoxins to inhibit both protein synthesis and colony formation was evaluated. Qualitatively similar results were obtained for both types of assays. Usually, PE conjugates were more toxic than their corresponding RTA conjugates. 454C11-PE was very toxic for all ovarian carcinoma lines, whereas 454C11-RTA had low activity. Both 260F9-PE and 260F9-RTA were active in all OVCAR cell lines but not in A1847 cells. 280D11-PE was toxic for OVCAR-4; otherwise, 280D11-PE and RTA conjugates of both 280D11 and 245E7 had little activity. Specificity of immunotoxin action was shown by competition by excess antibody, nontoxicity in nontarget cells, and inactivity of an irrelevant immunotoxin. To investigate the basis of antibody-dependent differences in activity of the various immunotoxins, antibody uptake was studied in OVCAR-2 cells, and the results indicate that antibody internalization is one important factor in the activity of immunotoxins.

ADP Ribose Transferases↗
PubMed1985

Anti-transferrin receptor antibody linked to Pseudomonas exotoxin as a model immunotoxin in human ovarian carcinoma cell lines.

The present in vitro study was performed to evaluate the potential usefulness of immunotoxins in treating human ovarian carcinomas. A monoclonal antibody against the human transferrin receptor was covalently linked to Pseudomonas exotoxin. The activity of this immunotoxin (anti-TFR-PE) was studied in five ovarian carcinoma cell lines, a breast carcinoma cell line (MCF-7), and in KB cells. The ovarian carcinoma cell lines included one previously established cell line (A1847) and four recent isolates obtained from the malignant ascites of patients with metastatic ovarian carcinoma (OVCAR cell lines). While all cell lines showed inhibition of protein synthesis by anti-TFR-PE, there were quantitative differences when the level of protein synthesis was assayed after a 12-hr incubation with the immunotoxin. These differences resulted from different kinetics of anti-TFR-PE activity in the various cell lines. Higher levels of cellular binding and internalization of anti-TFR were shown to contribute to increased toxicity of anti-TFR-PE. Verapamil increased the rate of protein synthesis inhibition and thus enhanced the toxicity of anti-TFR-PE in the OVCAR cell lines.

ADP Ribose Transferases↗
PubMed1985

Potentiation of cytotoxic activity of immunotoxins on cultured human cells.

The cytotoxic activity against human tumor cells of toxic conjugates of Pseudomonas exotoxin with anti-transferrin receptor antibody or epidermal growth factor was potentiated up to 10 to 20-fold by the calcium antagonists verapamil, D-600, and diltiazem and by the lysosomotropic agent beta-glycylphenyl-naphthylamide. The potentiating activity of these agents could be predicted by measuring the inhibition of protein synthesis by the immunotoxins on various cell lines. The use of potentiating agents such as these in combination with immunotoxins may prove useful in the treatment of some human cancers.

Antibodies, Neoplasm↗
PubMed1984

Prediction of the response to chemotherapy in acute leukemia by a short-term test in vitro.

To detect sensitivity or resistance of leukemic cells to chemotherapy prior to treatment, a short-term incubation method was employed. Blast cells from the peripheral blood or bone marrow of adult patients presenting with different forms of acute leukemia were analyzed for in vitro responsiveness to anticancer drugs in terms of suppression of 3H-uridine incorporation into cellular nucleic acids. The following agents were tested over a wide range of concentrations: Adriamycin, cytosine arabinoside, thioguanine, 6-mercaptopurine, prednisone, and 4-hydroperoxycyclophosphamide. Retrospectively, the in vitro data were compared to the clinical response of the patients to polychemotherapy. In the majority of the patients, in vitro cytotoxic effectiveness of Adriamycin (doxorubicin) and cytosine arabinoside reflected the in vivo situation. The levels of in vitro inhibition that could distinguish between drug-sensitive and drug-resistant diseases appeared to be 30% for Adriamycin and 20% for cytosine arabinoside. No correlation was found between the Adriamycin effect in vitro and the proliferative state (rate of 3H-thymidine incorporation) of the leukemic cell population. Serial in vitro sensitivity testing during the course of disease of various patients proved the ability of the test system to detect acquired resistance to chemotherapeutic agents. Therefore, the assay might serve as a reliable tool in the selection of effective chemotherapy in individual patients suffering from acute leukemia.

Acute Disease↗
PubMed1984

Short-term in vitro sensitivity testing in acute leukemia.

To detect sensitivity or resistance of leukemic cells to chemotherapy prior to treatment, a short-term incubation method was employed. Blast cells from the peripheral blood or bone marrow of adult patients with different forms of acute leukemia were analyzed for in vitro responsiveness to cytostatic agents in terms of suppression of nucleoside precursor (3H-uridine, 3H-deoxyuridine) incorporation into the cells. Retrospectively, the in vitro data were compared to the clinical response of the patients to polychemotherapy. In the majority of patients, in vitro cytotoxic effectiveness of doxorubicin and ara-C reflected the in vivo situation. The levels of in vitro inhibition that could distinguish between drug-sensitive and drug-resistant diseases appeared to be 30% for doxorubicin and 20% for ara-C. No correlation was found between the doxorubicin effect in vitro and the proliferative state of the leukemic cell populations. Serial in vitro testing during the course of the disease of various patients proved the ability of the test system to detect acquired resistance to chemotherapeutic agents. Studies with established cell lines (HL-60, Raji) indicated that the short-term test in its present form is probably not suited to monitor the effect of drug combinations in vitro.

Acute Disease↗
PubMedDate not supplied

Expression of the multidrug resistance protein (MRP1) in breast cancer.

BACKGROUND: The multidrug resistance protein (MRP1) is expressed in human breast carcinomas but its clinical significance remains unclear. The aim of the present study was to determine the clinical significance of MRP1 in breast cancer patients. MATERIALS AND METHODS: MRP1 expression of primary carcinomas from 100 breast cancer patients was immunohistochemically determined by means of the monoclonal antibodies QCRL-1/QCRL-3. RESULTS: MRP1 was negative in 20 (20%) and positive in 80 (80%) breast carcinomas. MRP1 expression was more frequent in both estrogen receptor-negative carcinomas and progesterone receptor-negative carcinomas (p = 0.1 in both cases), but was independent of tumor size and lymph node involvement. Patients with MRP1-negative carcinomas had prolongations of overall survival (p = 0.01 for death due to any cause, p = 0.04 for breast cancer-related death) and disease-free survival (p = 0.07) as compared to those with MRP1-positive carcinomas. Also in subsets of patients (negative lymph nodes; positive lymph nodes; positive estrogen receptor; T1/T2 tumors), overall survival was longer for patients with MRP1-negative carcinomas. In univariate Cox regression analyses, MRP1 positivity was associated with relative risks of 4.9 (95% CI 1.2-20.6; p = 0.03) for death due to any cause, 6.4 (95% CI 0.9-48.0; p = 0.07) for breast cancer-related death and 3.5 (95% CI 0.8-14.9; p = 0.09) for relapse. In multivariate Cox regression analyses, MRP1 positivity had relative risks of 5.1 (95% CI 1.2-21.7; p = 0.03) for death due to any cause, 6.5 (95% CI 0.8-50.1; p = 0.07) for breast cancer-related death and 3.4 (95% CI 0.8-15.1; p = 0.1) for relapse. CONCLUSIONS: Our results suggest that MRP1 might be an important factor in breast cancer indicating excellent prognosis for patients with MRP1-negative carcinomas.

ATP-Binding Cassette Transporters↗
PubMedDate not supplied

Expression of the lung resistance protein (LRP) in primary breast cancer.

BACKGROUND: To determine the clinical significance of the lung resistance protein (LRP) in breast cancer, we have studied its expression in primary breast carcinomas (n = 99) and assessed the association of this expression with clinical parameters of the patients. MATERIALS AND METHODS: LRP expression was immunohistochemically determined by means of the monoclonal antibody LRP-56 on frozen tumor sections. RESULTS: LRP expression was negative in 12%, low in 20%, intermediate in 47% and high in 21% of the carcinomas. LRP expression was independent of age of the patients, histology, tumor grade, estrogen receptor as well as progesterone receptor status, tumor size and lymph node involvement. Kaplan-Meier analyses revealed that both overall survival and disease-free survival were independent of the degree of LRP expression. CONCLUSIONS: LRP is frequently expressed in breast carcinomas, but is neither associated with known prognostic factors, nor a prognostic factor by itself.

Adult↗
PubMedDate not supplied

P-glycoprotein and MRP1 expression in axillary lymph node metastases of breast cancer patients.

BACKGROUND: Only little information on the expression of P-glycoprotein (P-gp) and MRP1 in metastases of breast carcinomas is currently available. The aim of the present study was to investigate the expression of these two proteins in axillary lymph node metastases of breast cancer patients. MATERIALS AND METHODS: We determined the expression of P-gp and MRP1 in axillary lymph node metastases of 63 breast cancer patients and, in 32 patients, compared this expression to the expression of corresponding primary tumors. P-gp was detected by means of C219 and Ab-2 monoclonal antibodies, and MRP1 by means of the MRPr1 monoclonal antibody. RESULTS: In lymph node metastases, P-gp expression was positive, usually at low levels, in 28 (44%) specimens whilst MRP1 expression was positive in all specimens with low, intermediate and high levels in 3 (5%), 46 (73%) and 14 (22%) specimens, respectively. The percentage of P-gp expression was slightly lower in lymph nodes than in primary tumors while MRP1 expression showed a higher staining intensity in lymph nodes than in their corresponding primary tumors. CONCLUSION: These data indicate that both P-gp and MRP1 are frequently expressed in lymph node metastases of breast cancer patients and that MRP1 expression is more pronounced in lymph node metastases than in corresponding primary tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Expression of the lung resistance protein in primary colorectal carcinomas.

To assess whether the lung resistance protein (LRP) is of clinical significance in colorectal carcinomas, we immunohistochemically determined LRP expression of colorectal carcinoma specimens (n = 68) by means of the monoclonal antibody LRP-56 and compared this expression with clinical parameters. LRP expression was negative in 7 (10%), low in 36 (52%) and high in 25 (38%) carcinomas. LRP expression was independent of histological grade, tumor size, lymph node involvement and distant metastasis. Survival of the patients with LRP-positive tumors was similar to the survival of patients with LRP-negative tumors. However, patients with high LRP expression in their carcinomas had a prolonged survival. Thus LRP is frequently expressed in colorectal carcinomas and high expression might indicate improved survival.

Aged↗
PubMedDate not supplied

Expression of folylpolyglutamyl synthetase predicts poor response to methotrexate therapy in patients with rheumatoid arthritis.

OBJECTIVE: The enzyme folylpolyglutamyl synthetase (FPGS) is involved in the resistance to methotrexate in tumor cell lines. The aim of the present study was to determine the impact of FPGS mRNA expression on resistance to methotrexate therapy in patients with rheumatoid arthritis (RA). METHODS: We determined the expression of FPGS mRNA using the Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) in 141 patients with RA. All patients received methotrexate therapy. The primary outcome measures were disease activity as determined by a disease activity score (DAS) and response to therapy. RESULTS: Seventy-eight of 141 patients (55%) showed expression of FPGS mRNA. FPGS mRNA expression was not associated with age, sex, disease duration, white blood cell count, erythrocyte sedimentation rate, C-reactive protein (CRP), number of swollen joints, number of painful joints, and combined therapy with other disease-modifying antirheumatic drugs (DMARDs) or additional corticosteroids. The response rate to methotrexate therapy was 44% for the total study population. Patients without FPGS mRNA expression showed a significantly higher response rate than patients with FPGS mRNA expression (57% versus 33%; p = 0.005). Multivariate logistic regression analysis revealed that female sex (p = 0.009) and FPGS mRNA expression (p = 0.004) were independent predictive factors for failure to achieve a response to methotrexate therapy. CONCLUSION: FPGS mRNA expression is an independent predictive factor associated with poor response to methotrexate therapy in RA patients.

Adult↗
PubMedDate not supplied

MDR1 gene expression in myelodysplastic syndrome and in acute myeloid leukemia evolving from myelodysplastic syndrome.

The expression of the MDR1 gene, a multidrug resistance gene, was determined in patients (N = 24) with myelodysplastic syndrome or acute myeloid leukemia evolving from it. MDR1 RNA expression of the mononuclear cells was detected in 14 (58%) patients. Among patients who had progressed to acute myeloid leukemia (sAML) (N = 14), MDR1 RNA expression was seen in 8 (57%) patients. Expression was observed in the 2 patients who had been pretreated with MDR drugs. These findings indicate that the MDR1 gene is frequently expressed in MDS or sAML and suggest that multidrug resistance might be involved in the clinical drug resistance of these diseases.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Relationship between MDR1 gene and surface markers in acute myeloid leukemia.

The MDR1 gene is of prognostic significance in acute myeloid leukemia (AML). The relationship of this gene to surface markers largely remains unclear. Therefore, we have studied the association of MDR1 gene expression with the expression of specific surface markers in AML. MDR1 RNA expression of leukemic cells was determined by slot blot analysis. Expression of P-glycoprotein and surface markers (CD7, CD13, CD19, CD34, HLA-DR, TdT, blood group H) was assessed by immunocytochemistry. MDR1 RNA (n = 79) and P-glycoprotein (n = 52) expression were detected in 63% and 63% of the patients, respectively. CD7, CD13, CD19, CD34, HLA-DR, TdT and blood group H were positive in 17%, 84%, 0%, 51%, 82%, 11% and 11% of the patients. MDR1 RNA or P-glycoprotein expression were not associated with the expression of either CD7, CD13, CD19, CD34, TdT or blood group H. However, P-glycoprotein expression was more frequent in HLA-DR positive than in HLA-DR negative patients (47% versus 10%, p = 0,04). Consistent with the latter finding, patients with intermediate or high MDR1 RNA expression expressed HLA-DR more frequently than patients with negative or weak MDR1 RNA expression (96% versus 76%, p = 0,03). In conclusion, MDR1 gene expression of AML cells was independent of surface markers except HLA-DR.

ATP Binding Cassette Transporter, Subfamily B, Mem↗