[Overcoming resistance in tumors].
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ATP Binding Cassette Transporter, Subfamily B, Mem↗
Biomedical subjects
M Volm
Publications and source records attributed to M Volm.
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↗
Expression of metallothionein in initial and relapsed childhood acute lymphoblastic leukemia.
In a retrospective study we analyzed the expression of metallothionein (MT) in initial acute lymphoblastic leukemia (ALL) of 92 children and in relapsed ALL of 27 children using immunohistochemistry. MT expression was detectable in 33% of the patients with initial ALL and in 33% of the patients with relapsed ALL. No differences were seen concerning the intensity and the proportion of positively stained cells between initial and relapsed patients. The expression of MT was independent of clinical prognostic factors such as age, sex, immunological subtype, and initial blast cell count. Patients with initial ALL and MT expression tended to have a lower probability of disease-free survival compared with the MT-negative group. The relapsed patients with MT expression showed also a trend toward a shorter survival in comparison to the MT-negative group. However, the differences were not statistically significant. Thus, the results show that MT expression is not an important prognostic factor in the clinical drug resistance of childhood All.
Child↗
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↗
P-glycoprotein and glutathione S-transferase pi in childhood acute lymphoblastic leukaemia.
Blast cells obtained from 104 children with untreated acute lymphoblastic leukaemia were analysed for the expression of P-glycoprotein (P-170) and glutathione S-transfer pi (GST-pi) using immunohistochemistry. Expression of P-170 was detected in 36 of 104 patients (35%) and increased GST-pi was seen in 52 patients (50%). Coexpression of both resistance proteins was observed in 22 leukaemias (21%), whereas no evidence of the resistance markers was found in 38 cases (37%). In patients with P-170-positive leukaemic cells, a significantly lower probability of remaining in first continuous complete remission (CCR) was observed when compared with patients with P-170-negative tumours (P < 0.05). However, only a trend for a more frequent expression of P-170 was found in the leukaemic cells of patients who experienced relapses (P = 0.099). Overexpression of GST-pi was correlated with a higher relapse rate (P = 0.001) and a lower probability of remaining in first CCR (P = 0.01). Expression of P-170 and GST-pi was independent of sex, FAB type, immunological subtype and initial blast cell count. The multivariate analysis indicated that only the expression of P-170 is an unfavourable prognostic factor for children with acute lymphoblastic leukaemia in addition to the prognostic clinical factors.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Reversal of doxorubicin-resistance in sarcoma 180 tumor cells by inhibition of different resistance mechanisms.
Resistance of tumor cells to doxorubicin is a multifactorial phenomenon. In the present investigation, the ability of resistance modifiers against different resistance mechanisms was analysed. Substances which block P-glycoprotein (P-170) function circumvented resistance of doxorubicin-resistant sarcoma 180 (S180) cells completely (verapamil, thioridazine) or partially (hycanthone), whereas inhibitors of glutathione S-transferase (ethacrynic acid, N-ethylmaleimide, buthionine sulfoximine), and protein kinase C (staurosporine, acridine orange) caused only a partial reversion of resistance. In contrast, an inhibitor of alkaline phosphatase (levamisole) did not overcome doxorubicin-resistance. These results indicate that P-glycoprotein blockers might be more effective to modulate doxorubicin-resistance of S180 cells as compared to other modifiers. Further investigations using other MDR cell lines are required to clarify the generality of these findings.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
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↗
Expression of oncoproteins in primary human non-small cell lung cancer and incidence of metastases.
In the current study the relationship between the incidence of metastatic spread and expression (at the protein level) of various proto-oncogenes was investigated in 217 human non-small cell lung carcinomas. Tumors with an overexpression of proteins encoded by the oncogenes c-jun and c-myc showed a significantly increased formation of metastases (c-jun: P = 0.008; c-myc: P = 0.018). No significant correlations were found between the expression of the c-fos, c-erbB1, c-neu and c-ras products and metastatic spread.
Carcinoma, Non-Small-Cell Lung↗
Prognostic significance of the expression of c-fos, c-jun and c-erbB-1 oncogene products in human squamous cell lung carcinomas.
The expression of the oncogenes c-fos, c-jun, c-myc, c-erbB-1 and c-erbB-2 at the protein level was analyzed in squamous cell lung carcinomas of 121 patients by means of immunohistochemistry. Patients with overexpression of proteins encoded by the oncogenes c-fos, c-jun and c-erbB-1 had significantly shorter survival times than these without overexpression of these oncogene products (c-fos: p = 0.009; c-jun: p = 0.029; c-erbB-1: p = 0.018). No significant correlations were found between the expression of c-myc and c-erbB-2 products and the survival of the patients. In addition to the univariate analyses (Kaplan-Meier-estimates) multivariate analyses (Cox-regression-model) revealed that protein expression of the oncogenes c-fos, c-jun and c-erbB-1 are significant prognostic factors in addition to staging.
Adult↗
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↗
Overexpression of oncoproteins in non-small cell lung carcinomas of smokers.
Non-small cell lung carcinoma specimens of 173 previously untreated patients were analyzed for the expression of proteins encoded by the oncogenes c-myc, c-fos, c-jun, c-erbB-1, c-erbB-2, c-H-ras, c-K-ras and c-N-ras. Forty-six per cent of the tumors were positive for the c-MYC protein, 60% for c-FOS, 50% for c-JUN, 80% for c-ERBB-1, 55% for c-ERBB-2, 12% for c-H-RAS, 5% for c-K-RAS and 71% for c-N-RAS. Proteins encoded by c-fos and c-jun are overexpressed more frequently in carcinomas of smokers (c-fos: P < 0.005; c-jun: P < 0.01). When we grouped the patients according to their tumor histology the results became more evident. Squamous cell lung carcinomas of smokers showed a higher incidence of c-FOS (P = 0.01), c-JUN (P < 0.01) and c-ERBB-1 (P = 0.01) proteins than squamous cell lung carcinomas of non-smokers. The expression rate and the intensity of staining proved not to be influenced either by the number of cigarettes smoked daily or by cessation of smoking. In adenocarcinomas, however, we only found a trend for a more frequent overexpression of c-fos (P = 0.07) and c-jun (P = 0.14) encoded proteins in carcinomas of smokers and no correlation between the expression of c-erbB-1 products and smoking. No correlation was found between the expression of c-MYC, c-ERBB-2, c-H-RAS, c-K-RAS and c-N-RAS proteins and the smoking habits of the patients, neither in squamous cell carcinomas nor in adenocarcinomas of the lung.
Adenocarcinoma↗
Increase of alkaline phosphatase in multidrug-resistant tumor cells and their cross-resistance to 6-thioguanine.
The expression of alkaline phosphatase (AP) was analyzed in multidrug-resistant (MDR) tumor cells (sarcoma 180, lung carcinoma, and renal cell carcinoma cell lines) by means of immunocytochemistry. MDR cell cultures showed an overexpression of AP and a cross-resistance to 6-thioguanine (6-TG, CAS 154-42-7). Significant correlations between AP expression and doxorubicin or vincristine resistance and P-glycoprotein (P-170) expression were found in these cell cultures. A specific AP inhibitor, levamisole, reversed resistance to 6-TG, but not to doxorubicin. This indicates that 6-TG resistance is certainly associated to P-170 but a causal function of AP for the development of MDR does not exist.
Alkaline Phosphatase↗
[The individualized therapy of tumors].
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Antineoplastic Agents↗
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↗
Antibody-directed therapy of multidrug-resistant tumor cells.
The major obstacle to effective cancer chemotherapy is the resistance of tumor cells to cytostatic agents. Tumor cells frequently express a multidrug-resistance (MDR) phenotype. In an effort to devise new strategies to overcome MDR, antibody-directed approaches for the eradication of MDR cells have been developed. Experimental data have shown that multidrug-resistant tumor cells can be efficiently killed by monoclonal antibodies, immunotoxins, or bispecific antibodies. The current experimental results indicate that an antibody-directed therapeutic approach to eradication of MDR cells might be a promising adjunct to conventional chemotherapy of cancer patients.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
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↗
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↗
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↗