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Biomedical subjects

J Mattern

Publications and source records attributed to J Mattern.

At least 55 records · Page 3Linked to original sources
PubMed1995

Resistance mechanisms in human lung cancer.

Drug resistance is an important problem in the treatment of lung cancer. Patients become resistant not only to the drugs used initially, but also to those to which they have not yet been exposed. Multiple mechanisms contribute to drug resistance in this disease, all or any combination of which may occur simultaneously within each cell, producing an overall drug-resistant phenotype. The limited success of hitherto applied strategies in their ability to circumvent drug resistance in lung cancer suggests that new approaches are required.

Antineoplastic Agents↗
PubMed1994

Cytotoxic T lymphocytes with a grafted recognition specificity for ERBB2-expressing tumor cells.

Experimental approaches which exploit the targeted cytolytic activity of lymphocytes are being developed for cancer therapy. We generated cytotoxic T lymphocytes (CTLs) with specificity for ERBB2 receptor-expressing tumor cells. A binding function was conferred directly on the zeta chain of the T-cell receptor (TCR) complex to circumvent major histocompatibility complex-restricted antigen recognition through the alpha and beta chains of the TCR. A chimeric gene was constructed which encoded a single-chain Fv antibody (scFv, consisting of the joined heavy- and light-chain variable domains of a monoclonal antibody against the extracellular domain of the ERBB2 receptor), a hinge region as a spacer, and the zeta chain of the TCR. This gene was introduced into CTLs by retroviral gene transfer. The signaling potential of the scFv/hinge/zeta receptors was demonstrated by secretion of interferon gamma upon coincubation with ERBB2-expressing cells. Target cells expressing the ERBB2 gene were lysed in vitro with high specificity by the scFv/hinge/zeta-expressing T cells. The growth of ERBB2-transformed cells in athymic nude mice was retarded by adoptively transferred scFv/hinge/zeta-expressing CTLs. Transduced CTLs labeled with a fluorescent dye were specifically detected in tumor sections. Our results suggest that tumor cell lysis by CTLs grafted in vitro with a major histocompatibility complex-independent recognition could become a gene-therapy approach to cancer treatment.

3T3 Cells↗
PubMed1994

Modulation of doxorubicin-toxicity by tamoxifen in multidrug-resistant tumor cells in vitro and in vivo.

Modulation of the resistance of tumors offers new strategies to improve the therapeutical treatment of cancer. In this report, the anti-oestrogen tamoxifen was investigated in multidrug-resistant tumor cells in vitro and in vivo. The doxorubicin-resistance of L 1210/DOX-tumor cells, which express the multidrug-resistance phenotype, could be completely circumvented by addition of 1 microgram/ml tamoxifen. In contrast, no increased effect could be observed in the parental L 1210 tumor cells or in cytosine arabinoside-resistant L 1210 cells not expressing the multidrug-resistance phenotype. Thus, the enhancing effect of tamoxifen was restricted only to the multidrug-resistant L 1210/DOX tumor cells. Similar to the in vitro experiments, a significant reduction in the growth in solid tumors of mice by the combined treatment of doxorubicin and tamoxifen was again observed only in the multidrug-resistant L 1210/DOX tumors.

Animals↗
PubMed1994

Analysis of c-fos, c-jun, c-erbB1, c-erbB2 and c-myc in primary lung carcinomas and their lymph node metastases.

The purpose of this study was to identify possible alterations in proto-oncogenes (c-fos, c-jun, c-erbB1, c-erbB2 and c-myc) at the protein level in primary lung carcinomas and simultaneous metastatic lymph nodes of 21 patients. The analysis showed that proteins of c-jun and c-myc were expressed in a significantly higher frequency in metastases than in primary lung tumors. Gross differences were not found between primary tumors and metastatic tumors with regard to the expression of c-erbB1, c-erbB2 and c-fos. The finding of cases with a higher expression of c-jun and c-myc in lymph nodes suggests that metastatic capability may be higher in certain cell populations.

Carcinoma↗
PubMed1993

Expression of resistance factors (P-glycoprotein, glutathione S-transferase-pi, and topoisomerase II) and their interrelationship to proto-oncogene products in renal cell carcinomas.

BACKGROUND: This study investigates whether or not an interrelationship exists between the expression of resistance-related proteins (P-glycoprotein, glutathione S-transferase, topoisomerase II) and proto-oncogene products (c-fos, c-myc, c-K-ras, epidermal growth factor receptor [EGF-R], and c-neu proteins.) METHODS: Thirty-eight human renal cell carcinomas of previously untreated patients were analyzed for expression of P-glycoprotein (P-170), glutathione S-transferase-pi (GST-pi), topoisomerase II (Topo II) and proto-oncogene proteins by means of immunohistochemistry. Because of significant heterogeneity in most tumor biopsies, all analyses were done on tumor-derived primary cell culture lines on the third or fourth passage. RESULTS: An interrelationship between increased expression of P-170 and GST-pi and down-regulation of Topo II was found. Expression of the c-fos protein was seen in 66% of the tumors; expression of the c-myc protein, in 50%; of the c-K-ras protein, in 16%; of the EGF-R protein, in 61%; and of the c-neu protein, in 54% of the tumors. A significant correlation between the resistance factors and the c-fos, EGF-R, and c neu-proteins was observed (GST/c-fos, P = 0.012; Topo II/c-fos, P = 0.024; P-170/EGF-R, P < 0.001; GST/EGF-R, P = 0.018; Topo II/EGF-R, P = 0.027; P-170/c-neu, P = 0.005; GST/c-neu, P = 0.018; Topo II/EGF-R, P = 0.027; P-170/c-neu, P = 0.005; GST/c-neu, P = 0.008; Topo II/c-neu, P = 0.05). In contrast, interrelationships between resistance proteins and c-myc and c-K-ras proteins were not found. A significant interrelationship between the investigated resistance-related proteins or proto-oncogene proteins and the stage or grading of the tumors was not observed. CONCLUSIONS: The results demonstrate that in renal cell carcinomas a significant relationship exists between resistance-related proteins, such as P-170, GST-pi, or Topo II, and proto-oncogenes, such as c-fos, c-erbB1, and c-neu.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Cephalic-phase insulin in obese and normal-weight men: relation to postprandial insulin.

Cephalic-phase insulin release (CPIR) and its relation to postprandial insulin release were examined in 18 normal-weight and 15 obese men. When the insulin data were expressed as absolute differences from baseline values, obese subjects exhibited significantly greater CPIR than normal-weight subjects (normals, 8.7 +/- 2.1 microU/mL/10 min; obese, 13.4 +/- 4.3 microU/mL/10 min; P < .01). Obese subjects were then separated into groups depending on their fasting insulin levels. This showed that only those subjects with elevated fasting insulin levels exhibited greater CPIR than normal subjects, and suggested that previous reports of exaggerated CPIR in the obese are merely a reflection of a basal hypersecretion of insulin. However, when insulin values were expressed as percentages of baseline, no significant differences between normal-weight and obese subjects were found, although a trend toward an attenuated response was observed in the obese group as a whole (normals, 81.6 +/- 19.1 microU/mL/10 min; obese, 51.3 +/- 16.1 microU/mL/10 min). A significant correlation between cephalic-phase and postprandial insulin release was found in normal-weight subjects (r = .62, P < .05), but not in obese subjects (r = .02, P < .9).

Adult↗
PubMed1993

High rate of expression of multidrug resistance-associated P-glycoprotein in human endometrial carcinoma and normal endometrial tissue.

The overexpression of P-glycoprotein was studied in 10 normal endometrial controls (five from the proliferative and five from the secretory phase of the menstrual cycle) and in 23 endometrial carcinomas of different histological varieties, using the C219 and JSB-1 monoclonal antibodies. Three of the tumours had been previously treated with combination chemotherapy containing doxorubicin. All endometrial carcinomas, whether treated or untreated, as well as the normal endometrial controls from both the proliferative and the secretory phase of the menstrual cycle, overexpressed P-glycoprotein. This puts endometrial carcinoma into the same category as other tumours arising in organs which normally overexpress P-glycoprotein, all of which tend to be intrinsically resistant to chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Relationship of inherent resistance to doxorubicin, proliferative activity and expression of P-glycoprotein 170, and glutathione S-transferase-pi in human lung tumors.

BACKGROUND: This study analyzed whether proliferative activity and expression of P-glycoprotein 170 (P-170) or glutathione S-transferase-pi (GST-pi) in human non-small cell lung carcinomas (NSCLC) represent independent factors in resistance to doxorubicin or whether an association exists between these factors. METHODS: Thirty-six patients with previously untreated NSCLC participated in the study. The thymidine labelling index (TLI) was measured for detection of proliferative activity, and immunohistochemistry was used for detection of P-170 and GST-pi. The resistance of tumors was determined in vitro by the nucleotide incorporation assay. RESULTS: Negative correlations between TLI and P-170 (P = 0.0009) or GST-pi (P = 0.007) were found. Positive correlations existed between resistance to doxorubicin in vitro and P-170 (P = 0.005) or GST-pi (P less than 0.0001). Expression of P-170 and GST-pi showed highly significant (P less than 0.0001) positive correlation. CONCLUSIONS: The results demonstrate that a significant positive relationship between P-170 and GST-pi in NSCLC exists and that the expression is increased in resistant tumors and in tumors with a low proliferative activity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Immunohistochemical detection of the multi-drug-resistance marker P-glycoprotein in uterine cervical carcinomas and normal cervical tissue.

Uterine cervical carcinomas and normal cervical tissue (controls) were investigated for the presence of the multi-drug-resistance gene product P-glycoprotein by means of immunohistochemistry, with the C219 monoclonal antibody and the streptavidin-biotin-peroxidase technique. Ten of 11 cervical carcinomas, 2 of which were previously treated with chemotherapeutic agents of the multi-drug-resistance group, showed a positive reaction of tumor cells. All normal controls showed a positive reaction of the ectocervical and endocervical epithelial cells. P-glycoprotein seems to be implicated at least in part in resistance to chemotherapy of cervical carcinoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Expression of topoisomerase II, catalase, metallothionein and thymidylate-synthase in human squamous cell lung carcinomas and their correlation with doxorubicin resistance and with patients' smoking habits.

Forty-eight human squamous cell lung carcinomas of previously untreated patients were analyzed for resistance to doxorubicin and for the presence of topoisomerase II (Topo II), metallothionein (MT), thymidylate synthase (TS) and catalase (Cat). Significant correlations exist between resistance to doxorubicin measured by the in vitro short-term test and overexpression of MT and TS measured by immunohistochemistry. No significant correlation was found between resistance and expression of Topo II or Cat. No significant interrelationship between smoking habits of patients and expression of Topo II, MT, TS or Cat was found.

Adult↗
PubMed1992

Immunohistochemical detection of P glycoprotein, glutathione S transferase and DNA topoisomerase II in human tumors.

The expression of the drug resistance markers P glycoprotein (P-170), glutathione S transferase-pi (GST-pi) and DNA topoisomerase II (Topo II) was analyzed in 16 human kidney carcinoma cell lines, 18 hematological malignancies, and 14 human breast carcinomas. We found a tendency for coexpression of increased P-170 and GST-pi and of increased P-170 and decreased Topo II expression in kidney carcinoma cell lines. A similar tendency was found between P-170 and GST-pi expression in breast carcinomas. In contrast, hematological malignancies did not show such a coexpression of resistance markers. Furthermore, we found interrelationships between the expression of resistance markers, resistance to doxorubicin or vincristine, and doubling times of kidney carcinoma cell lines. This indicates that the proliferative activity of tumor cells plays a role for the expression of resistance markers and the development of resistance to cytostatic drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Resistance mechanisms in murine tumors with acquired multidrug resistance.

Mechanisms of multidrug resistance were studied in murine leukemia (L 1210) and sarcoma (Sa 180) tumors after pretreatment with anthracyclines in vivo. Despite identical pretreatment protocols, a considerable difference in the level of resistance between L 1210 and Sa 180 tumors was noted (for doxorubicin: 45-fold versus 340-fold; for daunorubicin: 51-fold versus 275-fold). However, no difference in mdr 1 gene-amplification and the overexpression of mdr 1-RNA or P-glycoprotein was demonstrated. None of these parameters did increase by further treatment with a higher concentration of anthracyclines. Resistant sublines of Sa 180 revealed an overexpression of glutathione S-transferase-pi (GST-pi) in comparison to the parental line, whereas in sensitive and resistant sublines of L 1210 tumors the expression of GST-pi was similar. In order to study whether trifluoperazine can reverse the P-glycoprotein mediated component of multidrug resistance, trifluoperazine and doxorubicin were tested in vitro in L 1210 and Sa 180 cells. In contrast to the complete reversal of resistance in L 1210 tumors, resistance in Sa 180 was only partly circumvented. However, by buthionine sulfoximine treatment, the toxicity of multidrug resistant Sa 180 tumors could be increased. It was possible to reverse the resistance of Sa 180 tumors completely by trifluoperazine plus buthionine sulfoximine. Thus, multidrug-resistant Sa 180 tumors express different defense mechanisms whereas L 1210 tumors express only one defense mechanism (P-glycoprotein).

Animals↗
PubMed1991

[The prevalence of cytostatic-resistant lung tumors in smokers].

The resistance of tumours against doxorubicin was determined in vitro and compared with their smoking habits in 94 patients (81 males and 13 females; mean age 59 [38-76] years) with non-small-cell lung tumour. Among non-smokers (n = 22) 11 tumours were resistant and 11 sensitive, while among smokers (n = 72) 57 (79%) were resistant and only 15 (21%) sensitive to doxorubicin. P-glycoprotein was measured immunohistochemically and with the monoclonal antibody JSB-1 in order to test whether there is a relationship between the prevalence of resistant tumours among smokers and the expression of P-glycoprotein. Among 22 nonsmokers only two tumours (9%) were P-glycoprotein positive, but among 72 smokers, 42 tumours (58%) were positive (P less than 0.0001). Thus, the increased amount of resistant non-small-cell lung tumours in smokers can be explained partially by an increased expression of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Circumvention of multi-drug resistance in human kidney and kidney carcinoma in vitro.

This report investigated whether the calmodulin inhibitor, trifluoperazine, can circumvent multi-drug resistance both in primary tissue cultures of human kidney and kidney carcinoma. For detection of inherent multi-drug resistance, the expression of P-glycoprotein was determined by immunofluorescence and immunocytochemistry using the monoclonal antibody C219. For detection of doxorubicin resistance and reversal of this resistance by trifluoperazine, the incorporation of nucleic acid precursor was measured after addition of doxorubicin and trifluoperazine, respectively. Both P-glycoprotein expressing resistant normal and malignant kidney tissue cultures could be modified by trifluoperazine. However, sensitive normal kidney and kidney carcinoma cultures were little affected by trifluoperazine. Thus, circumvention of primary resistance to doxorubicin is not limited to tumor cells. This might have important implications for the use of resistance modifiers in the clinical setting.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Overexpression of P-glycoprotein and glutathione S-transferase-pi in resistant non-small cell lung carcinomas of smokers.

Ninety-four human non-small cell lung carcinomas (NSCLC) of previously untreated patients were analysed for the presence of P-glycoprotein (P-170) and glutathione S-transferase-pi (GST-pi) by means of immunohistochemistry. The expression of P-170 and GST-pi was compared with the results of doxorubicin resistance of the tumours in vitro and the smoking habits of the patients. A significant relationship between smoking habits of the patients and resistance of NSCLC was found (P = 0.007). Of the 72 tumours of smokers 57 (= 79%) were resistant, whereas of the 22 tumours of non-smokers only 11 (= 50%) showed resistance. Identical results were obtained when the analysis was restricted to patients with epidermoid lung carcinomas (P = 0.004). In contrast to these data, there exists no relationship between resistance and smoking for adenocarcinomas of the lung. Forty-two (= 58%) out of the 72 NSCLC of smokers expressed P-170, whereas out of 22 tumours of non-smokers only two tumours (= 9%) showed P-170 expression (P less than 0.0001). Similar results were obtained with epidermoid carcinomas (P = 0.004) and adenocarcinomas (P = 0.027). Fifty (= 69%) of 72 NSCLC of smokers revealed expression of GST-pi, whereas only nine (= 41%) of 22 tumours of non-smokers showed GST-pi expression (P = 0.015). Significant correlations also exist between resistance in vitro and expression of P-170 (P less than 0.0001) or expression of GST-pi (P less than 0.0001). Furthermore, a significant relationship between both proteins could be demonstrated (P less than 0.0001).

ATP Binding Cassette Transporter, Subfamily B, Mem↗