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Biomedical subjects

R Pirker

Publications and source records attributed to R Pirker.

At least 55 records · Page 3Linked to original sources
PubMed1994

MDR1 gene expression in chronic lymphocytic leukemia.

In order to assess the clinical role of the MDR1 gene in chronic lymphocytic leukemia (CLL), we determined its expression in the leukemic cells of 39 patients with CLL and compared this with other clinical and laboratory parameters. MDR1 RNA expression was detected in 29 patients. MDR1 RNA transcripts were independent of age, treatment status of the patients and the clinical stage of CLL, but correlated with the white blood cell count and MDR2 RNA transcripts. Expression of the tumor suppressor gene p53 was found in 30 out of 37 patients and was associated with MDR1 RNA expression (P < 0.001). Immunocytochemistry using the monoclonal antibody C219 was performed in 38 patients, and in 28 cases, more than 5% of the leukemic cells were found to express cell surface P-glycoprotein. P-glycoprotein expression correlated with the expression of MDR1 RNA (P = 0.048).

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

P-glycoprotein expression as unfavorable prognostic factor in acute myeloid leukemia.

In order to further define the role of the MDR1 gene in acute myeloid leukemia (AML), we determined the association between the presence of P-glycoprotein on leukemic cells and the efficacy of therapy in patients with AML. Immunocytochemistry with monoclonal antibody C219 was performed to demonstrate the presence of P-glycoprotein. Positive staining ranged from 0 to 60% of the leukemic cells. For further analysis, patients were assigned into groups with 0-5% staining cells (group 1, n = 33) and with > 5% staining cells (group 2, n = 19). The complete remission rate of induction chemotherapy was 76% for group 1 but only 32% for group 2 (p = 0.002). The median duration of overall survival was 19 months for patients in group 1 as compared to 3 months for patients in group 2 (p = 0.007). The data indicate that P-glycoprotein expression is associated with an unfavorable prognosis in patients with AML.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

MDR1 gene expression and its clinical relevance in primary gastric carcinomas.

BACKGROUND: Drug resistance remains a major problem in gastric carcinomas. To evaluate the mechanisms involved in this resistance, the authors determined the expression of the MDR1 gene, a multidrug resistance gene, in primary gastric carcinomas. METHODS: MDR1 RNA levels of gastric carcinoma specimens (n = 22) were determined by slot blot analysis. An MDR1 cDNA (probe 5A) was used for the hybridization. RESULTS: MDR1 RNA was detected in 41% of the gastric carcinomas, with high levels in 18% of the specimens. No expression of the MDR3 gene was observed in these tumors. MDR1 gene expression was independent of patient age, tumor localization, and lymph node involvement. However, MDR1 RNA expression was less frequent in locally advanced tumors and was absent in the primary tumors of all six patients who had distant metastases. CONCLUSIONS: The data indicate that multidrug-resistant cells are present in primary gastric carcinomas and suggest that multidrug resistance might contribute to the clinical drug resistance of these tumors.

Adenocarcinoma↗
PubMed1993

Effective second line chemotherapy of advanced breast cancer with navelbine and mitomycin C.

The efficacy and toxicity of navelbine 30 mg/m2 administered intravenously (IV) over 30 minutes every 3 weeks, and mitomycin C 15 mg/m2 administered IV every 6 weeks was assessed in 34 patients with metastatic breast cancer refractory to first-line chemotherapy. An overall objective response rate of 35% was achieved (95% confidence interval, 20% to 53%), with an additional 47% of patients maintaining stable disease (SD). Four of 12 patients who responded had received previous anthracycline therapy. Median time to progression for responders and patients with SD was 6.3 months. The median survival of all patients was 8.8 months. Tolerance of this regimen was remarkable. WHO grade 3/4 side effects consisted of granulocytopenia in 12% and thrombocytopenia in 15%, and included only 1 patient each with grade 3 neurotoxicity and local toxicity due to extravasation. Delay of treatment was required for hematologic toxicity in 7 patients, and 5 required dose reductions. In conclusion, navelbine/mitomycin C is an active and well-tolerated regimen that may be considered for second-line treatment. If our results are confirmed by larger analyses of other patients studies, this combination might also warrant further exploration in combination with other active agents for front line chemotherapy of advanced breast cancer.

Adult↗
PubMed1993

MDR1 gene expression in primary colorectal carcinomas.

The expression of the MDR1 gene, a multidrug resistance gene, was prospectively determined in 113 primary colorectal carcinoma specimens and correlated with clinical data including survival durations of the patients. MDR1 RNA was detected in 65% of the carcinomas. No expression of the MDR2 gene was seen, MDR1 gene expression was independent of age and sex of the patients, size and histologic grading of the tumour, lymph node involvement and distant metastasis. Kaplan-Meier analysis revealed that the durations of both relapse-free survival and overall survival were not different between patients with MDR1 RNA positive tumours and those with MDR1 RNA negative tumours.

Adenocarcinoma↗
PubMed1993

MDR1 RNA expression as a prognostic factor in acute myeloid leukemia: an update.

In order to confirm our initial report on the negative impact of MDR1 gene expression on the outcome of de novo acute myeloid leukemia (AML), we present an update of our prospective study with a larger number of patients and a longer duration of follow-up. At diagnosis, MDR1 RNA expression of the leukemic cells was negative in 37% and positive in 63% of the patients (N = 79). The complete remission rate of induction chemotherapy was 76% for MDR1 RNA negative and 54% for MDR1 RNA positive patients (p = 0.05). At a median observation duration of 33 months, the duration of overall survival was 19 months for the MDR1 RNA negative patients but only 8 months for the patients with MDR1 gene expression (p = 0.02). Thus the long-term data also indicate that MDR1 gene expression is an unfavourable prognostic factor in AML.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Adaptation of mouse leukemia cells L1210 to vincristine. Evidence for expression of P-glycoprotein.

A vincristine resistant cell line was obtained from mouse leukemia cells L1210 by long-term adaptation in a medium with stepwise increasing concentrations of vincristine. By Western blotting using monoclonal antibody C219, positive signal on the presence of P-glycoprotein was observed in the resistant cells. Moreover, hybridization of mRNA from vincristine resistant cells with radiolabeled MDR1 cDNA probe gave evidence about the expression of MDR1 gene. The observed resistance may be depressed by application of "chemosensitizers" such as (1) calcium entry blockers (verapamil and nifedipine); (2) neuroleptics (trifluorperasine) and (3) local anesthetics (lidocaine) directly to the grow medium. Any significant effect in O2 consumption as well as incorporation of [U-14C]-glucose by the sensitive or resistant cells was not detected in the absence of vincristine. Presence of vincristine induced increasing velocity of O2 consumption by resistant cells from 2.5 +/- 0.3 to 3.3 +/- 0.2 microliters/min.10(6) cells, and, on the other hand, decreasing O2 consumption by sensitive cells from 2.3 +/- 0.2 to 1.7 +/- 0.1 ml/min.10(6) cells. The presence of vincristine induced less potent decrease in glucose incorporation by resistant cells in comparison with values which were observed in sensitive cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

MDR1 gene expression and treatment outcome in acute myeloid leukemia.

To prospectively assess the role of MDR1 gene expression in patients with de novo acute myeloid leukemia (AML), levels of MDR1 RNA in blast cells were determined at diagnosis and correlated with treatment outcome in 63 patients. MDR1 RNA levels were negative in 29% and positive in 71% of the patients. The complete remission rate in response to induction chemotherapy was 89% for MDR1 RNA-negative patients and 53% for MDR1 RNA-positive patients (P = .008). Expression of the MDR1 gene was observed in most patients who died early or had resistant disease. Kaplan-Meier curves revealed a decrease in both disease-free survival and overall survival of patients with detectable MDR1 gene expression compared with the disease-free survival and overall survival of MDR1 RNA-negative patients (P = .029 and P = .009, respectively). These data indicate that MDR1 gene expression is an unfavorable prognostic factor and suggest that multidrug resistance is important in AML.

Adolescent↗
PubMed1991

MDR1 gene expression and prognostic factors in primary breast carcinomas.

To prospectively assess the role of the MDR1 gene in breast carcinomas, MDR1 RNA levels of breast carcinoma specimens were determined by slot blot analysis. In 59 evaluable patients with primary breast carcinomas, MDR1 RNA levels of the carcinomas were negative in 54%, low in 29% and high in 17% of the patients. No differences in age, menopause status, oestrogen and progesterone receptor levels, tumour size, lymph node involvement and c-erbB-2/neu gene expression were observed between MDR1 RNA negative patients and MDR1 RNA positive patients.

Adult↗
PubMed1990

Reversal of multi-drug resistance in human KB cell lines by structural analogs of verapamil.

Several structural analogs of verapamil were studied for their ability to reverse multi-drug resistance (MDR) in human KB cell lines. D595, D792 and verapamil completely reversed resistance to colchicine and adriamycin. D595 and D792 had a higher reversing potency than verapamil. Devapamil, gallopamil, emopamil and D528 partially reversed MDR. The reversing potency of a drug did not correlate with its calcium antagonistic activity. No differences in reversing potency between (R)-isomers, (L)-isomers and the racemic forms were observed in the case of both verapamil and emopamil. (R)-verapamil, which has less calcium antagonistic activity and less in vivo toxicity than racemic verapamil, and D792, which has higher reversing potency and less in vivo toxicity than racemic verapamil, should be suitable for clinical applications to overcome drug resistance in cancer patients.

Cell Survival↗
PubMed1990

Experimental treatment of chronic lymphocytic leukemia with extracorporeal photochemotherapy. Initial observations.

Based on the encouraging results obtained with extracorporeal photochemotherapy (EP) in the treatment of the exfoliative erythrodermic form of cutaneous T-cell lymphoma (CTCL), leukemic form, as well as other T-cell-mediated diseases we evaluated the therapeutic potential of EP in patients with chronic lymphocytic leukemia (B-CLL). Three patients with B-CLL were treated for a period of 1 year. Two patients showed stabilization of disease, as demonstrated by reduction in their peripheral white blood cell count, with one patient showing lymph-node resolution. A third patient with significant intolerance to previous chemotherapy did not respond within the observed period. No significant side effects of EP were observed. Our observations suggest that EP may have a positive effect on the course of B-CLL in selected patients. Additional clinical trials are warranted to further define the role of EP alone or in combination therapy in the management of B-CLL.

Adult↗
PubMed1989

Enhancement of the activity of immunotoxins by analogues of verapamil.

Verapamil has been shown to enhance immunotoxin activity but only at concentrations that are too high for in vivo use. Therefore, four structural analogues of verapamil (D792, D595, D528, and Sz45) were evaluated for their ability to enhance the in vitro activity of immunotoxins made with either ricin A chain or Pseudomonas exotoxin. The following immunotoxins were used: HB21-PE and 454A12-rRTA which recognize the human transferrin receptor; and 260F9-rRTA which reacts with human ovarian carcinoma and breast carcinoma cells. The activities of the immunotoxins were determined in ovarian carcinoma cells and in KB cells using inhibition of either protein synthesis or colony formation as a measure for the cytotoxicity of the immunotoxins. Each of the four analogues enhanced the activity of ricin A-immunotoxins in a dose-dependent manner. D792 and D595 also increased the activity of IIB21-PE. Low concentrations of either Sz45 or D528 enhanced the activity of HB21-PE, but high concentrations of these two analogues either had less enhancing potency than low concentrations or even decreased the activity of HB21-PE. Specificity of enhancement by the analogues was shown by competition of the activity of the immunotoxins by the corresponding antibody and by inactivity of an irrelevant immunotoxin. The amount of enhancement ranged from 2-fold to greater than 60-fold and was dependent on the cell line and on the experimental conditions. The enhancing ability of the drugs did not correlate with their calcium-antagonistic activity. When compared with verapamil, D792 and D595 had greater enhancing potency with regard to both ricin A-immunotoxins and Pseudomonas exotoxin-immunotoxins. Greater enhancing potency and less in vivo toxicity makes D792 a candidate for use in the enhancement of immunotoxins in vivo.

ADP Ribose Transferases↗
PubMed1989

Expression of a multidrug resistance gene in human cancers.

Many cancers have been cured by chemotherapeutic agents. However, other cancers are intrinsically drug resistant, and some acquire resistance following chemotherapy. Cloning of the cDNA for the human MDR1 gene (also known as PGY1), which encodes the multidrug efflux protein P-glycoprotein, has made it possible to measure levels of MDR1 RNA in human cancers. We report the levels of MDR1 RNA in greater than 400 human cancers. MDR1 RNA levels were usually elevated in untreated, intrinsically drug-resistant tumors, including those derived from the colon, kidney, adrenal gland, liver, and pancreas, as well as in carcinoid tumors, chronic myelogenous leukemia in blast crisis, and cell lines of non-small cell carcinoma of the lung (NSCLC) with neuroendocrine properties. MDR1 RNA levels were occasionally elevated in other untreated cancers, including neuroblastoma, acute lymphocytic leukemia (ALL) in adults, acute nonlymphocytic leukemia (ANLL) in adults, and indolent non-Hodgkin's lymphoma. MDR1 RNA levels were also increased in some cancers at relapse after chemotherapy, including ALL, ANLL, breast cancer, neuroblastoma, pheochromocytoma, and nodular, poorly differentiated lymphoma. Many types of drug-sensitive and drug-resistant tumors, including NSCLC and melanoma, contained undetectable or low levels of MDR1 RNA. The consistent association of MDR1 expression with several intrinsically resistant cancers and the increased expression of the MDR1 gene in certain cancers with acquired drug resistance indicate that the MDR1 gene contributes to multidrug resistance in many human cancers. Thus, evaluation of MDR1 gene expression may prove to be a valuable tool in the identification of individuals whose cancers are resistant to specific agents. The information may be useful in designing or altering chemotherapeutic protocols in these patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

VMCP chemotherapy with or without interferon-alpha-2 in newly diagnosed patients with multiple myeloma.

Fifty-two previously untreated patients with multiple myeloma were randomized to either a combination of recombinant interferon (rIFN) alpha-2 and chemotherapy or chemotherapy alone. Patients were treated with vincristine, melphalan, cyclophosphamide and prednisolone every 4-6 weeks. In the combined treatment arm rIFN was administered concurrently with chemotherapy as well as during chemotherapy free intervals. The combined regimen effected 17/21 (80.9%) responses as compared to 19/27 (70.4%) responses in VMCP treated patients. Addition of rIFN to chemotherapy did not enhance hematologic toxicity. These findings suggest a somewhat higher rate of objective response in the VPMC + rIFN group, although a significant improvement in median survival by adding rIFN to conventional first line polychemotherapy in myeloma patients has not yet been achieved.

Adult↗
PubMed1988

Enhancement of the activity of immunotoxins made with either ricin A chain or Pseudomonas exotoxin in human ovarian and epidermoid carcinoma cell lines.

The present study evaluates whether the in vitro activity of immunotoxins can be enhanced by verapamil or by various antagonists of calmodulin (dansylcadaverine, trifluoperazine, chlorpromazine). The following immunotoxins made with either Pseudomonas exotoxin (PE), recombinant ricin A chain (rRTA), or ricin A chain (RTA) were used: HB21-PE and 454A12-rRTA that both recognize the human transferrin receptor; and 260F9-rRTA and 454C11-RTA that both react with human ovarian and breast cancer cells. The cytotoxicity of these immunotoxins was determined in human ovarian carcinoma cell lines and KB cells. Verapamil, that was demonstrated previously to enhance the cell-killing activity of PE immunotoxins, enhanced the activity of several ricin A chain immunotoxins, including 454A12-rRTA, 260F9-rRTA, and 454C11-RTA. Comparing 50% inhibitory dose values for inhibition of protein synthesis by 454A12-rRTA, enhancement ranged from 2- to greater than 25-fold, was dependent on the concentration of verapamil, and was greatest at short incubation times. In addition, the cytotoxicity of HB21-PE and of selected RTA immunotoxins was increased up to 30-fold by the addition of various calmodulin antagonists. The enhancing drugs did not decrease the specificity of the immunotoxins.

ADP Ribose Transferases↗