Biomedical subjects

M Volm

Publications and source records attributed to M Volm.

At least 271 records · Page 15Linked to original sources

PubMedDate not supplied

Cellular predictive factors for the drug response of lung cancer.

The main objective of this study to analyze which of 31 cellular factors (resistance proteins, proliferative factors, apoptotic factors, angiogenic factors, proto-oncogenes) most accurately predict the resistance of non-small cell lung carcinomas. To this purpose, we used a short-term in vitro test that measures changes in the rate at which radioactive nucleic acid precursors are incorporated into tumor cells after the addition of doxorubicin to determine the response to doxorubicin in 94 non-small cell lung carcinomas. The results obtained by the short-term test were related to the various cellular factors which were in turn determined by immunohistochemistry and flow cytometry. A significant correlation was found between the data obtained by the short-term test and the expression of P-glycoprotein 170 (P = 0.00004), glutathione-S-transferase-pi (P = 0.0002), metallothionein (P = 0.0008), thymidylate synthase (P = 0.002), O6-methylguanine-DNA-methyltransferase (P = 0.008) and lung resistance-related protein (LRP, P = 0.03). There was only a weak correlation between heat shock proteins (HSP70) and no correlation between the expression of topoisomerase II or catalase and the short-term test results. To measure the proliferative activity, the following were determined: PCNA, cyclin A, cyclin D and cdk2. Only a weak relationship was found between the expression of cdk2 (P = 0.04) and PCNA (P = 0.05) and the doxorubicin response in vitro. Of the investigated pro-apoptotic factors (Fas/CD95, Fas ligand, caspase-3), only Fas/CD95 is significantly associated with the drug response (P = 0.007). The apoptotic index also reveals a significant correlation (P = 0.03). Angiogenesis, as measured by the microvessel density and the angiogenic factors, is inversely correlated to the resistance of non-small cell lung cancer. Platelet-derived endothelial cell growth factor (PD-ECGF) and vascular endothelial growth factor (VEGF) exhibit a significant relationship to the drug resistance (P = 0.0006 and P = 0.004, respectively). Of the investigated proto-oncogenes (Fos, Jun, ErbB-1, ErbB-2, Myc, Ras), only ErbB-2 is weakly associated with the in vitro short term test. In order to determine whether combining factors can result in improved predictive information, combinations of the factors (pairs, triplets) were analyzed. The systematic investigation of these combinations yields an improvement in the predictive information. With one factor up to 76.6% of the tumors, with two factors up to 85.4% and with three factors up to 89.5% of the tumors could be correctly diagnosed.

Antibiotics, Antineoplastic↗

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

[Effect of cytoplasmic and serum factors on the uptake of (3H) thymidine-triphosphate (TTP) by isolated nuclei of liver cells].

The actions of cytoplasm (ultracentrifuged supernatant 105 000 times g) and of serum on the DNA synthesis (uptake of (3H) TTP) by isolated nuclei of liver cells were studied. Cytoplasm from liver cells obtained at various intervals after partial hepatectomy revealed a variable effect only with isolated nuclei of liver cells from partially hepatectomized rats. Cytoplasm obtained from liver cells eight hours after partial hepatectomy failed to show the usual inhibitory effect. Presumably the inhibitory substances normally present in cytoplasm are inactivated within a certain time after partial hepatectomy. Serum of partially hepatectomized animals enhanced the uptake of (3H) TTP by nuclei of normal liver cells and those from partially hepatectomized animals. The stimulating effect was present only in the serum obtained between four and twelve hours after partial hepatectomy. It remains unclear whether the effects described are growth factors specific for the liver.

Animals↗

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

Expression of protein kinase C in human renal cell carcinoma cells with inherent resistance to doxorubicin.

The expression of protein kinase C (PKC) was analyzed in 18 primary cell cultures of human renal cell carcinomas by means of immunocytochemistry. We found that a high PKC expression significantly correlates with both resistance to doxorubicin and high P-glycoprotein expression. These data support the hypothesis that PKC is involved in inherent drug-resistance by phosphorylation and regulation of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

[Studies on the specific effects of serum and cytoplasm of the liver on the [3H]TTP-incorporation of isolated liver nuclei (author's transl)].

Previous authors have described that liver cytoplasm and serum from partially hepatectomized rats stimulate the DNA synthesis of isolated nuclei of liver cells. The aim of our investigation was to prove whether such stimulating effects are part of a specific regulation of growth. The sera and the cytoplasm supernatant 105000 x g) were isolated at several intervals after partial hepatectomy and laparotomy and were tested on isolated nuclei of liver cells from adult rats partially hepatectomized 20 hours before. The supernatants isolated at 8 and 16 hours after both partial hepatectomy and laparotomy have a significant stimulatory effect on the [3H]TTP-uptake by nuclei. The presence of serum (10%) causes a general elevation (75%) of the [3H]TTP-uptake by isolated nuclei. The sera isolated 4 to 12 hours after operation from both partially hepatectomized and laparotomized rats have an additional stimulatory effect on the [3H]TTP-uptake synthes of nuclei. In no case did the sera and liver cytoplasm of partially hepatectomized rats have a significantly different and therefore "specific" effect on the nuclear DNA synthesis. Additional experiments showed that frozen and thawed nuclei of liver cells respond only to the nutritive power but not to the stimulatory effects of the sera. Thus, thawed nuclei cannot be used for growth investigations.

Animals↗

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

Reciprocal correlation between expression of P-glycoprotein and accumulation of rhodamine 123 in human tumors.

The aim of this investigation was to determine whether a correlation exists between expression of the multi-drug-resistance associated P-glycoprotein 170 (P-gp170) and the accumulation of rhodamine 123 in human tumors. We investigated a panel of inherently resistant cell lines originating from human kidney tumor specimens and chemotherapeutically pretreated leukemias. The expression of P-gp170 was evaluated by means of two different immunohistological methods using two monoclonal antibodies against P-gp170. We found a significant reciprocal correlation between expression of P-gp170 and accumulation of rhodamine 123. This supports the view that P-gp170 might function as efflux pump in human tumors, as previously described for experimental models.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

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↗

PubMedDate not supplied

Relevance of DNA-fluorimetry and short-term resistance testing for adjuvant treatment of non-small cell lung carcinomas.

In a clinical study 127 patients with previously untreated stage III non-small cell lung carcinomas (NSCLC) were investigated using flow cytometry and an in vitro short-term test for predicting resistance to cytostatic agents. Patients with aneuploid tumors and tumors with high proliferative activity had significantly shorter survival times than those with diploid or low proliferating tumors. The aim of this study was to find out whether groups of patients classified according to the additionally observed prognostic factors, experience an advantage or disadvantage from particular modalities of treatment. Seventy-nine patients had surgery alone, 18 patients were treated additionally with chemotherapy, and 30 patients with radiation. Patients with aneuploid, low proliferating and in vitro resistant tumors showed no different survival rates after treatment with chemo- and radiotherapy adjuvant to surgery. In contrast, patients with high proliferating tumors died earlier under adjuvant chemotherapy and radiation. Patients with in vitro chemosensitive tumors had shorter survival times after irradiation than patients who had surgery alone or who were treated with adjuvant chemotherapy.

Adult↗