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Biomedical subjects

M Volm

Publications and source records attributed to M Volm.

At least 91 records · Page 5Linked to original sources
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↗
PubMed1992

Immunocytochemical detection of oncoproteins in animal and human tumor lines with acquired or inherent multidrug resistance.

In this presentation, we analyze the relationship between protein expression of the protooncogenes c-fos, c-erb B1, c-K-ras, and c-myc and acquired or inherent multidrug resistance (MDR) in a panel of animal (CHO, S 180, L 1210) and human (KTCTL 44, KTCTL 18, CX 1, CXF 94) tumor lines by means of immunocytochemistry. Increased expression of c-fos and c-erb B1 proteins is a constant feature of all resistant cell lines except L 1210 cells, which did not reveal any alteration in oncoprotein expression. No apparent relationship between c-K-ras and c-myc proteins and MDR was found. The immunocytochemical results were corroborated by radioimmunoassays (RIAs). The data indicate that c-fos and c-erb B1 might play a role in the development of MDR.

Adenocarcinoma↗
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↗
PubMed1991

Overexpression of P-glycoprotein in human lung carcinoma xenografts after fractionated irradiation in vivo.

In vivo exposure of a human epidermoid lung carcinoma xenograft to seven irradiation treatments of 10 Gy in consecutive passages resulted in expression of resistance to vincristine. This about threefold drug resistance was detectable with a single dose of 1 mg/kg vincristine. Characterization of the radiation-pretreated subline showed that overexpression of P-glycoprotein, as determined by immunofluorescence and Mabs C219 and 265/F4, occurred in this tumor. After six X-ray fractions, only single positive cells were observed, whereas seven fractions produced an intense immunofluorescent reaction with both antibodies. Southern blot analyses indicated that no gene amplification had occurred. This result shows that irradiation can influence expression of P-glycoprotein and in this way influences drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

[Reversal of multidrug resistance with (R)-verapamil in vitro and in vivo].

The clinical use of racemic (R/S)-verapamil (CAS 52-53-9) as resistance modifier is limited because of the cardiovascular activity of the substance. The stereoisomer (R)-verapamil shows significant less cardiovascular activity. Therefore we tested the resistance modifying abilities of (R)-verapamil and (R/S)-verapamil in murine multidrug-resistant L 1210 ascites-tumor-cells in vitro and in vivo. The present results demonstrate, that the (R)-isomer has the same resistance modifying effects as racemic verapamil. Both modifying substances have no effects in the parental (sensitive) and cytosine-arabinoside resistant L 1210 ascites-tumor-cells. Thus, (R/S)-verapamil and (R)-verapamil show their resistance modifying abilities only in multidrug-resistant tumor-cells.

Animals↗
PubMed1990

Activity of various amphiphilic agents in reversing multidrug resistance of L 1210 cells.

Several compounds (bamipine, chlorphenoxamine, estracyt, hycanthone, quinidine, quinine, tamoxifen, trifluoperazine and verapamil) have a common basic structure with the following features: lipophilic aromatic ring system; linked chain hydrophilic N-alkyl group. They are used medically for varying diseases. Their activity in reversing multidrug-resistance (MDR) with other compounds (diethylstilbestrol, beta-estradiol, methylbiguanide, methylpiperazine, testosterone) lacking one of these chemical features is compared. The in vitro test system we used was the nucleoside incorporation assay using parental L 1210 ascites tumor cells and a doxorubicin resistant subline, which expresses the MDR phenotype. The substances lacking one of these features were not effective in reversing the MDR whereas all other tested substances demonstrated modulating potential in the MDR resistant L 1210 cells.

Animals↗
PubMed1990

Relationship of DNA ploidy to chemoresistance of tumors as measured by in vitro tests.

To examine whether patients with aneuploid tumors might derive more benefit from chemotherapy than would patients with diploid tumors, predictive tests for determining resistance in human tumors were carried out and the test results compared with the DNA ploidy of the corresponding tumors. Multidrug-resistance in 15 kidney carcinomas grown as primary cultures was determined by immunofluorescence by Mab C219, which is specific for the plasma membrane glyco-protein P-170, and by the use of tritiated nucleotide incorporation after addition of doxorubicin. Aneuploid tumors had a higher tendency to be more sensitive than diploid tumors, but the correlation was not significant. This was confirmed by reanalyzing our earlier data on ovarian and lung cancers. In conclusion, DNA measurement using flow cytometry does not appear to be a suitable tool for prediction of resistance of human tumors to chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Correlations between natural resistance to doxorubicin, proliferative activity, and expression of P-glycoprotein 170 in human kidney tumor cell lines.

The natural resistance to doxorubicin of 15 human renal carcinoma cell lines was analyzed and compared to proliferative activity and expression of P-glycoprotein. We found a significant negative correlation between proliferative activity and natural resistance to doxorubicin, as well as between proliferative activity and the expression of P-glycoprotein. A positive correlation between resistance and expression of P-glycoprotein was found.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

DNA analysis, chemoresistance testing and hormone receptor levels as prognostic factors in advanced ovarian carcinoma.

Fifty patients with advanced (stage III or IV) ovarian carcinoma were followed-up until the date of their death or their fifth year of survival. Prognostic factors, including those currently in use, as well as ploidy and proliferation, chemoresistance testing and hormone receptor levels of the tumours were analysed for predictive value and independence from each other. In the univariate analysis, only stage, residual tumour, second-look status, chemoresistance, ploidy and proliferation were significantly correlated with survival. After being tested in a multivariate Cox regression model, however, only the results of chemoresistance testing at initiation of therapy, and second-look status at a later point, retained prognostic significance. Within the group of patients with a positive second-look, i.e., with the worst prognosis, the chemoresistance test was still able to discriminate between two subgroups with significantly different survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Overexpression of P-glycoprotein in rat hepatocellular carcinomas induced with N-nitrosomorpholine.

The most frequently reported alteration of multidrug resistance (MDR) is the overexpression of the 170 kd membrane glycoprotein. An increased expression of the MDR-gene in pre-neoplastic and neoplastic liver lesions produced experimentally by different carcinogens has been reported. As shown in rat liver by stop experiments, specific carcinogen-induced alterations can be separated from non-specific, toxic changes. Therefore, we induced rat hepatocellular carcinomas with N-nitrosomorpholine and investigated whether expression of the MDR-gene also takes place in hepatocellular carcinomas after withdrawal of the carcinogen. Using mAb C219 against P-glycoprotein, both normal liver and hepatocellular carcinomas show specific immunoreactivity by means of immunofluorescence and immunohistochemistry. In hepatocellular carcinomas, however, the reaction is increased if compared to normal liver of untreated control animals. These results were confirmed by immunoblotting. Using the cDNA probe 1.5, a significant increase in MDR-gene transcripts was found in hepatocellular carcinomas as compared to normal liver.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Detection of drug resistance and P-glycoprotein in human renal cell carcinomas.

Expression of the multidrug-resistance gene product P-glycoprotein (P-170) was screened in 21 untreated human renal cell carcinomas using monoclonal antibodies (265/F4, C219) and immunoperoxidase staining. The inherent drug resistance of the same samples against doxorubicin was established by a short-term chemoresistance test in order to investigate the association between the expression of P-170 and intrinsic drug resistance in kidney cancers. P-glycoprotein could be demonstrated in 10 cases. Using the short-term test for predicting resistance, 17 resistant and 4 sensitive cancers were found. In vitro 10 of 17 resistant tumors revealed an increase of P-glycoprotein. On the other hand, in the sensitive tumor in vitro, an expression of P-glycoprotein could not be demonstrated. This investigation reveals that intrinsic drug resistance exists in many renal cell carcinomas and it is associated at least in part with increased expression of P-glycoprotein. The immunohistochemical results suggest that the presence of the P-glycoprotein may be useful as a marker for screening the multidrug-resistant phenotype in renal cell carcinomas and as an indicator of the therapeutic efficacy of multidrug-resistant kidney cancers.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

[Prognostic significance of DNA ploidy and distribution of cell cycle phases in non-small cell bronchial cancer. A 5-year survival study].

Non-small cell lung carcinomas represent a mixed group of tumors with overlapping histologies, clinical courses and responses to treatment. Thus, an accurate prediction of tumor progression and patient survival remains a major problem for these tumors. The aim of the present study, therefore, was to look for cellular prognostic indicators in addition to the well known clinical prognostic factors. Fresh surgical specimens of tumors of 187 patients with previously untreated non-small cell lung carcinomas were investigated by means of flow cytometry. Patients with aneuploid tumors had significantly shorter survival times than did those with diploid tumors. Patients with tumors with a high proliferative activity died significantly earlier than patients with lower proliferative activity. Identical results are obtained when the analysis is restricted to just those patients with T3 tumors or to patients with metastatic tumors at time of surgery or were classified Stage III. These data indicate that DNA ploidy and distribution of cell cycle phase are strong and independent prognostic factors for the survival of patients with non-small cell lung carcinoma. All patients had a minimum of 5 years follow up.

Carcinoma, Non-Small-Cell Lung↗