Immunohistochemical Analysis of Pulmonary and Pleural Tumors with the Monoclonal Antibody HYB-612 Directed against the Multidrug Resistance (MDR-1) Gene Product, P-Glycoprotein

Radosevich, James A.; Robinson, Philip G.; Rittmann-Grauer, Lana; Wilson, Byron E.; Leung, Julia P.; Maminta, M.L.; Warren, William H.; Rosen, Steven T.; Gould, Victor E.

doi:10.1159/000217622

Cited by 21 publications

(8 citation statements)

References 12 publications

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“…immunohistochemistry, for assessing P-170 expression in human tumours. Radosevich et al (1989) found P-170-expressing cells in 100 out of 131 non-small cell lung carcinomas (= 76%) by immunohistochemical techniques. Lai et al (1989) demonstrated a weak expression of P-glycoprotein mRNA in 14 out of 24 lung tumours (= 58%).…”

Section: Resultsmentioning

confidence: 93%

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

Volm

Mattern²,

Samsel³

1991

Br J Cancer

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Summary 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-n (GST-i) by means of immunohistochemistry. The expression of P-170 and GST-ir 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 <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-w, whereas only nine (=41 %) of 22 tumours of non-smokers showed GST-i expression (P = 0.015). Significant correlations also exist between resistance in vitro and expression of P-170 (P<0.0001) or expression of GST-i (P<0.0001). Furthermore, a significant relationship between both proteins could be demonstrated (P<0.0001).During the past few years the phenomenon of multidrugresistance (MDR) has been thoroughly analysed and some of its molecular aspects clarified. The MDR-phenotype is characterised by cross-resistance between hydrophobic compounds without structural or functional similarities. The connection between MDR and the expression of a 170 kDa membrane glycoprotein (P-glycoprotein) has been clearly established in different tumour models (Riordan et al., 1985). The most direct evidence of the role of the P-glycoprotein (P-170) in resistance has come from studies that have demonstrated that resistance can be conferred through transfer of genetic material encoding P-glycoprotein (Gros et al., 1986;Sugimoto & Tsuruo, 1987). However, not all resistant tumours overexpress P-170 and refractoriness to chemotherapy can only partly be explained by P-170. Batist et al. (1986) described an elevated expression of glutathione S-transferase-ic (GST-i ) in doxorubicin-resistant MCF-7 cells. Alterations in nuclear DNA topoisomerase II (Topo II) content have been also reported in doxorubicin-resistant P388 cells (Deffie et al., 1989). Interestingly, Fairchild et al. (1987) observed an overexpression of both P-170 and GST-i in doxorubicinresistant MCF-7 cells. This raises the question as to whether the expression of those two proteins may be under a common regulatory control.In an earlier study with 160 human lung tumours (Volm et al., 1990a) we demonstrated that there is a significant relationship between smoking and response to doxorubic...

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Section: Resultsmentioning

confidence: 93%

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

Volm

Mattern²,

Samsel³

1991

Br J Cancer

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“…Two randomised trials in untreated small cell lung cancer (Wheeler et al, 1988;Milroy et al, 1991) have not shown significant benefit from adding oral verapamil to chemotherapy, although the larger study reported an overall increase in complete response rate and a longer median survival in patients with extensive disease who received verapamil (Wheeler et al, 1988). Small cell lung cancer is significantly less likely to express P-glycoprotein in untreated cases than non-small cell lung cancer (Radosevich et al, 1989) as is reflected in the high response rate of untreated small cell lung cancer to chemotherapy. The strategy of potentially circumventing MDR in small cell lung cancer by giving ifosfamide to patients who did not achieve a complete response after three cycles of MDR selecting drugs (etoposide, vincristine and doxorubicin) met with only limited success (Cantwell et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

“…Others have analysed tumour samples for the presence of P-glycoprotein immunohistochemically and found P-glycoprotein expressing cells in 76% (Radosevich et al, 1989) and 47% (Volm et al, 1991) (Tsuruo et al, 1981). Clinical studies have used verapamil given by intravenous infusion to produce the highest attainable plasma concentrations until limited by cardiovascular toxicity (Ozols et al, 1987;Miller et al, 1991).…”

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confidence: 99%

Oral verapamil with chemotherapy for advanced non-small cell lung cancer: a randomised study

1994

Lung Cancer

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Summary To determine if the chemotherapy resistance of non-small cell lung cancer could be modified by oral verapamil, 72 patients were entered into a randomised trial of verapamil plus chemotherapy vs the same chemotherapy alone. Verapamil 480 mg day-' was given for 3 days starting 24 h prior to chemotherapy which consisted of bolus vindesine 7 mg followed by ifosfamide/mesna 5 g m 2 over 24 h, followed by mesna alone for a further 8 h. Cycles were repeated every 3 weeks for up to six courses. Sixty-six patients were eligible for tumour response analysis and responses occurred in 41% of those randomised to chemotherapy plus verapamil and in 18% of those randomised to chemotherapy alone (P = 0.057). Median survival from start of treatment was significantly better in the verapamil arm (P = 0.02). Toxicity of the combination of chemotherapy plus verapamil was principally neurological and was manageable. Thus the addition of oral verapamil to vindesine/ ifosfamide chemotherapy is feasible and in this study was associated with improved outcome. Further confirmation of these observations is required in non-small cell lung cancer, a tumour characterised by resistance to conventional chemotherapy.

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“…Radosevich et al [33] found P-glycoprotein-expressing cells in 100 out of 131 non-small-cell lung carcinomas by immunohistochemical tech niques. In contrast to these results, other authors have only oc casionally detected expression of the P-glycoprotein gene in lung tumors [34].…”

Section: Discussionmentioning

confidence: 99%

Detection of Multiple Resistance Mechanisms in Untreated Human Lung Cancer

Volm¹,

Mattern²

1993

Oncol Res Treat

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Background: The aim of the study was to analyze whether or not a short-term test is able to detect drug resistance of tumors caused by various resistance mechanisms. Materials and Methods: The drug resistance of 94 human non-small-cell lung carcinomas was measured using an in vitro short-term test. Its basic feature is measurement of changes in the incorporation of radioactive nucleic acid precursors into cell suspensions made from fresh tumor biopsies after addition of doxorubicin. The expression of P-glycoprotein, glutathione S-transferase ττ, topoisomerase II, catalase, thymidylate synthase, and metallothionein was assessed immunohistochemically using alcohol-fixed paraffin-embedded sections. Results: Significant correlations were found between the results of the short-term test and the increased expression of P-glycoprotein, glutathione S-transferase ττ, thymidylate synthase, and metallothionein. In 44% of the doxorubicin-resistant tumors all four resistance-related proteins were detected; in 85% of the doxorubicin-resistant tumors more than one of these proteins were detected. The probability of detecting resistance by an in vitro short-term test increases with the number of resistance-related proteins in the tumor. Conclusion: The in vitro short-term test may thus help to detect different resistance mechanisms.

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Immunohistochemical Analysis of Pulmonary and Pleural Tumors with the Monoclonal Antibody HYB-612 Directed against the Multidrug Resistance (MDR-1) Gene Product, P-Glycoprotein

Cited by 21 publications

References 12 publications

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

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

Oral verapamil with chemotherapy for advanced non-small cell lung cancer: a randomised study

Detection of Multiple Resistance Mechanisms in Untreated Human Lung Cancer

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