Biomedical subjects

J Mattern

Publications and source records attributed to J Mattern.

At least 163 records · Page 9Linked to original sources

PubMedDate not supplied

PD-ECGF, bFGF, and VEGF expression in non-small cell lung carcinomas and their association with lymph node metastasis.

The angiogenic factors PD-ECGF, bFGF and VEGF were determined immunohistochemically in 168 non-small cell lung carcinomas to investigate whether the expression of these parameters is correlated with lymph node metastasis of patients. The expressions of the above mentioned factors was indeed associated with lymph node metastasis, but the results were not statistically significant. However, a combination of the factors PD-ECGF, bFGF and VEGF significantly improved the prognostic information. The number of tumors with lymph node involvement increased with the number of angiogenic factors. Only 43% of the patients had-lymph node involvement when all factors were negative whereas 77% showed metastasis when all factors were positive (one factor positive: 53%, two factors positive: 68). This result is statistically significant (p = 0.002, test for trend).

Adenocarcinoma↗

PubMedDate not supplied

Angiogenesis and cigarette smoking in squamous cell lung carcinomas: an immunohistochemical study of 28 cases.

Angiogenesis in tumors is influenced by several factors which in turn are associated with chemoresistance or radioresistance. Moreover, the tumors of smokers are known to be relatively resistant to chemotherapy. This investigation attempts to determine whether or not a relationship exists between cigarette smoking and angiogenesis in lung cancer. Tumor samples from 14 non-smokers and 14 heavy cigarette smokers were selected for this study. The populations were matched for age, sex and tumor stage. Resistance to doxorubicin, microvessel density, the expression of vascular endothelial growth factor (VEGF) and thrombospondin (TSP) were analyzed in both populations. Tumors of smokers were more frequently resistant to doxorubicin in vitro, had lower vessel counts and a reduced expression of VEGF compared to tumors of nonsmokers. In contrast, TSP was significantly increased in the tumors of smokers. These data show that angiogenesis in lung tumors is linked to a patient's smoking habits.

Carcinoma, Squamous Cell↗

PubMedDate not supplied

Inverse correlation between apoptotic (Fas ligand, caspase-3) and angiogenic factors (VEGF, microvessel density) in squamous cell lung carcinomas.

In order to explore whether apoptosis is associated with angiogenesis in lung cancer, immunohistochemistry was employed to determine the pro-apoptotic factors Fas ligand (FasL) and caspase-3 (Cas-3) in 70 squamous cell lung carcinomas. Furthermore, the vascular endothelial growth factor (VEGF) and the microvessel density (MVD) were analyzed. The comparison between MVD and the pro-apoptotic factors demonstrated that the apoptotic factors are inversely related to MVD (Cas-3: p = 0.011, FasL: not significant). In order to confirm this result, FasL and Cas-3 were also compared with the expression of VEGF. Again, an inverse correlation between VEGF and the pro-apoptotic factors was found (Cas-3: p = 0.019, FasL: p = 0.008). The inverse correlation between angiogenesis and apoptosis may be explained by the activation of pro-apoptotic and anti-angiogenic factors caused by hypoxia.

Adult↗

PubMedDate not supplied

Xenotransplantability of human squamous cell lung cancer in nude mice is not affected by angiogenic factors.

Sixty-two human squamous cell lung carcinomas were analyzed for expression of various angiogenic growth factors and their receptors using immunohistochemistry. The data were correlated with xenotransplantability of these tumors in nude mice. None of the factors investigated did show an association with xenotransplantability. However, there was a trend that specimens lacking VEGF165 were established as xenografts at a higher incidence (52%) than those expressing VEGF165 (39%).

Adult↗

PubMedDate not supplied

Glucose-related protein (GRP78) and its relationship to the drug-resistance proteins P170, GST-pi, LRP56 and angiogenesis in non-small cell lung carcinomas.

Several studies have documented that induction of the glucose-related protein (GRP78) is associated with the development of drug-resistance to antitumor drugs. However, nothing has been reported concerning GRP78 in human lung tumors and its relationship to several resistance proteins and angiogenesis. Therefore, this study analyzed the expression of GRP78 in a series of 62 consecutive lung cancer patients and examined whether or not a relationship exists between GRP78, several resistance proteins and microvessel density (MVD). Secondary, it evaluated the relationship of GRP78, LRP56 and GST-pi in cancer cell lines under hypoxic conditions and in sensitive and resistant cell lines. We determined that a relationship exists between GRP78 and the resistance proteins P170, LRP56 and GST-pi in human lung cancer. Furthermore, we observed an up-regulation of GRP78 in the resistant cell lines LUTC-ML54, OAW-Dox and OAW-Tax, but not in sensitive cell lines. Abnormal vascularization of malignant tumors is associated with the development of hypoxic regions. In hypoxic regions, several proteins, including drug resistance proteins, are expressed in greater quantities. Our study detected an inverse correlation between GRP78 and MVD. Carcinomas with low MVD exhibited a higher expression of GRP78. Furthermore, protein expression of GRP78, GST-pi and LRP56 increased in the cell lines A-549, RPMI-2650 and SC-MES-1 under hypoxic conditions. These observations suggest that hypoxia, tumor vascularization and the simultaneous expression of many resistance-related proteins, including GRP78, may play an important role in drug response and therapeutic effectiveness.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Role of angiogenesis in drug resistance.

Tumor angiogenesis seems to be an important factor in determining therapeutic effectiveness and patient prognosis. An abundance of data on tumor angiogenesis is available and it clearly shows that most human solid tumors are heterogeneously vascularized and oxygenated and contain hypoxic regions. Such regions and areas of reduced vascularization can affect the response to a variety of drugs. Direct measurements of angiogenesis in various types of tumors have, upon correlation of the data with therapeutic outcome, shown that a high vascular density is associated with a decreased response to therapy and short overall survival time. Therefore, the extent of tumor angiogenesis may well be an important factor contributing to the difficulty of successful therapy in certain tumor types.

Animals↗

PubMedDate not supplied

Clinical estimation of the growth rate of lung cancer.

It is well known that the growth rate of lung tumors is closely related to prognosis and is an important determinant of responsiveness to therapy and curability. In this study, the velocity of tumor growth was calculated by dividing the area of the lesion at presentation divided by the time elapsed since symptoms were first noted. This parameter was applied to a group of patients with lung cancer and the predictive value of the velocity of tumor growth was assessed. Survival expectancy was found to be closely related to the growth rate of the tumors. The median survival time of patients with more slowly growing tumors was 102 weeks, while that of patients with fast-growing tumors was 30 weeks (log-rank test, p=0.00001). Linear regression analysis between velocity of tumor growth and tumor cell proliferation as measured by the PCNA-labelling index revealed a significant correlation between these two parameters. In conclusion, the velocity of a tumor measured in this way is an independent and significant prognostic factor for patients with lung cancer and may be used to non-invasively assess lung cancer proliferation in vivo, identifying rapidly growing tumors with poor prognosis that could benefit from a more aggressive therapy.

Adult↗

PubMedDate not supplied

Elevated expression of thymidylate synthase in doxorubicin resistant human non small cell lung carcinomas.

Human non-small cell lung carcinomas of previously untreated patients were analyzed for expression of thymidylate synthase (TS) using immunohistochemistry. Of the 94 tumors, 67 were positive for TS and 27 negative. A significant correlation between the expression of TS and the resistance to doxorubicin was found (p < 0.0001). Eighty-four percent of the TS-positive tumors were resistant to doxorubicin, whereas of the 27 TS-negative tumors only 44 percent were resistant. A group of patients (n = 13) were treated with combination chemotherapy including 5-fluorouracil, doxorubicin and cisplatinum. Seven of the 8 tumors which were TS-positive were clinically progressive, whereas 4 of 5 tumors which were TS-negative showed clinical remission after chemotherapy (p < 0.05; Fisher exact test). The patients whose tumors were TS negative lived significantly longer than those with TS-positive tumors. The median survival times were 185 weeks for patients with TS-negative and 41 weeks for patients with TS-positive tumors (p < 0.05; log-rank-test). Thus the expression of TS is a strong prognostic factor for resistance of tumors, clinical course and survival of patients with non-small cell lung carcinomas.

Adenocarcinoma↗

PubMedDate not supplied

Oncoprotein (c-myc, c-erbB1, c-erbB2, c-fos) and suppressor gene product (p53) expression in squamous cell carcinomas of the lung. Clinical and biological correlations.

The expression of the protooncogene encoded proteins (c-erbB1, c-erb B2, c-myc, c-fos) and the suppressor gene product p53 was analyzed in 81 human squamous cell carcinomas of the lung and correlated with clinical parameters of the patients (patient survival, presence of metastases and tumor stage) and with biological characteristics of the tumors (tumor growth in nude mice, DNA-ploidy, proliferative activity, drug-resistance and P-glycoprotein or gluathione S-transferase expression). By means of immunohistochemistry, expression of c-erbB1 oncoprotein (EGF-receptor) was detected in 79% of the tumors, c-erbB2 (c-neu) proteins in 35%, c-myc proteins in 48%, c-fos proteins in 41%, and p53 in 43% of the tumors. Patients with c-erbB1 positive tumors had a poor prognosis (p = 0.021). In addition, these tumors were more frequently drug resistant (p = 0.0067). A significant correlation between the growth of the squamous lung carcinomas in nude mice and c-fos oncoprotein expression was demonstrated (p = 0.017). Therefore, EGF-receptor and c-fos products may serve as prognostic factors for the aggressiveness of squamous cell carcinomas of the lung and for the response of these tumors to chemotherapy. No significant correlation was found between the expression of the c-erbB1 or c-fos gene products and stage, metastasis and DNA-ploidy. In contrast to these results, no relationship was found between c-neu or c-myc gene products expression and any of the clinical or biological parameters examined. Aneuploid squamous cell carcinomas of the lung expressed p53 more frequently than diploid tumors (p = 0.027). However, there was no significant difference between p53 expression and stage, survival of patients, metastasis, growth of the tumors in nude mice, proliferative activity and drug-resistance of the tumors.

Carcinoma, Squamous Cell↗

PubMedDate not supplied

Prediction of drug resistance in human tumors using immunohistochemical techniques.

An in vitro chemosensitivity testing procedure based on the immunodetection of protein products which reflect the expression of various tumor resistance mechanisms is proposed. This protocol may be of predictive value in choosing drugs which should be selected for chemotherapy, and avoiding drugs which might be expected to be ineffective due to the enhanced expression of specific resistance factors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Expression of several resistance mechanisms in untreated human kidney and lung carcinomas.

Thirty human renal cell carcinomas and 94 non-small cell lung carcinomas of previously untreated patients were analyzed for the presence of P-glycoprotein, glutathione S-transferase-pi and topoisomerase II by means of immunohistochemistry. In the renal cell carcinomas investigated, two resistance markers were seen in 53% and three resistance markers in 36% of the cases. In only three tumors was one resistance mechanism observed. In the 94 non-small cell lung carcinomas 34% had two and 20% three resistance mechanisms, whereas 24% of the tumors revealed only one resistance mechanism. For determining the resistance of the tumors against drugs an in vitro short-term test was used. Only 12% of the sensitive lung tumors had more than one resistance mechanism, whereas 70% of the resistant tumors did. Thus a significant relationship exists between the resistance measured in vitro and the overexpression of P-glycoprotein or glutathione S-transferase-pi and the down-regulation of topoisomerase II.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Time course of MDR gene amplification during in vivo selection for doxorubicin-resistance and during reversal in murine leukemia L 1210.

MDR gene expression in murine leukemia L 1210 cells was investigated during treatment in vivo with 0.5 mg doxorubicin/kg body weight (BW). Drug resistance (measured by an in vitro short-term test and immunohistochemistry) increased with the number of treatments and the maximum resistance reached after 8 treatments was similar with that of an established multidrug- resistant cell line (20 treatments, 2 mg/kg BW). Southern-blot and DNA dot-blot analyses show that development of MDR is associated with MDR-gene amplification and correlates with the degree of drug resistance and P-glycoprotein-expression. After cessation of doxorubicin treatment, resistance decreased continuously and disappeared after 20 passages. This decrease in resistance is accompanied by a loss of MDR gene amplification and P-glycoprotein expression. Furthermore, P-glycoprotein expression was analyzed in the first hours after treatment with doxorubicin in vivo (0.5 mg/kg BW). Expression was markedly increased and peaked at about 24 hours after treatment. In contrast, only slightly increased resistance and no MDR gene amplification could be detected.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Reversing multidrug resistance in L1210 tumor cells by hycanthone or chlorophenoxamine in vitro and in vivo.

In the presence study we demonstrated that hycanthone and chlorophenoxamine can modulate the resistance of multidrug resistant (MDR) murine L1210 leukemia tumor lines in vitro and in vivo. The circumvention of MDR by hycanthone and chlorophenoxamine in vitro was demonstrated by a short-term test using tritiated nucleic acid precursors and by flow cytometrical measurement of accumulation of rhodamine 123. Furthermore, we treated mice bearing resistant L1210 ascites cells with doxorubicin and hycanthone or chlorophenoxamine. Hycanthone in combination with doxorubicin significantly inhibited tumor growth. We also found an improved therapeutic effect of doxorubicin plus chlorophenoxamine. Our results in vitro and in vivo indicate that hycanthone and chlorophenoxamine might be appropriate tools for the circumvention of MDR in human tumors.

Animals↗

PubMedDate not supplied

Intrinsic and acquired multidrug resistance in human lung carcinomas grown in nude mice.

Human epidermoid lung carcinoma xenografts with intrinsic and induced resistance were analyzed with regarding to different parameters. The xenografts with intrinsic resistance to vincristine (HXL 54) and induced drug-resistance sublines to vincristine (HXL 55/VCR), actinomycin D (HXL 55/AD) and cisplatin (HXL 55/DDP) were characterized in terms of the degree of resistance, cross-resistance, proliferation kinetics, tumorigenicity, keratin and P-glycoprotein expression. The results demonstrate that xenografts with intrinsic or induced resistance to vincristine or actinomycin D exhibit a similar general pattern of cross-resistance to that observed in multidrug-resistant cell lines. The resistance cannot be attributed to differences in proliferation kinetics. Development of resistance is associated with loss of tumorigenicity and features of differentiation, P-glycoprotein is little expressed in the resistant xenograft lines and corresponds well with the low grade of resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Maintenance of morphology and tumour marker production in human epidermoid lung carcinoma xenografts.

The histopathology and the expression of various marker substances including cytokeratin, epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA) of ten human epidermoid lung carcinoma xenograft lines were compared with the corresponding donor patient tumours. It was found that the histological structure and the tumour markers were maintained by the xenografts. Neoplastic cells were more effectively detected using anti-keratin antibodies as compared to antibodies against EMA. CEA immunoreactivity was more common in well differentiated tumours. With the aid of electron microscopy, the known cellular heterogeneity of epidermoid lung carcinomas in man was also confirmed in these xenografts.

Animals↗

PubMedDate not supplied

Quantitative analysis of resistance and cross-resistance to cytotoxic agents by tumour cell lines.

The published literature describing the spectrum of resistance and cross-resistance to cytotoxic agents by human and murine tumour cell lines maintained in long-term culture is reviewed. The data available demonstrate that for many cytotoxic agents, especially those of higher molecular weight, cross-resistance is proportional to the degree of resistance against the selecting agent. Furthermore, the degree of cross-resistance correlates with the molecular weight of the drug in adriamycin-, vincristine- and colchicine-resistant cell lines.

Animals↗

PubMedDate not supplied

Sensitivity of human non-small cell lung cancer xenografts to cyclophosphamide and cisplatin.

In order to establish the usefulness of the nude-mouse human tumour xenograft system as a predictive screen for antineoplastic agents, the antitumour activity of cyclophosphamide (CTX) and cisplatin (DDP), two clinically active drugs, was tested against a panel of 14 human non-small cell lung tumour xenografts and the experimental results were compared with the clinical results reported in the literature. The poor clinical response of non-small cell tumours was reflected in the lack of response of the xenograft tumours to these two agents.

Animals↗

PubMedDate not supplied

Immunocytochemical detection of a resistance-associated glycoprotein in tissue culture cells, ascites tumors and human tumor xenografts by Mab 265/F4.

The aim of this investigation was to find out whether resistant cells of different tumors can be detected immunocytochemically by the streptavidin-biotin-peroxidase-complex method using the monoclonal antibody 265/F4. This antibody was prepared against the membrane P-glycoprotein of Mr 170 kd from colchicine-resistant CHO cells. For this purpose the acquired resistance of tissue culture cells, ascites tumors and the acquired and inherent resistance of human lung carcinoma xenografts were analyzed. Doxorubicin-resistant S180 cells, daunorubicin-resistant L1210 cells and vincristine-resistant human epidermoid lung carcinoma xenografts showed an intense positive reaction with the monoclonal antibody. In contrast, no specific immunoreactivity was observed with parental (sensitive) tumor cells. These data could eventually provide a prognostic tool for the detection of resistant human tumor cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗