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Biomedical subjects

M Volm

Publications and source records attributed to M Volm.

At least 109 records · Page 6Linked to original sources
PubMed1989

Initial and early effects of adriamycin in murine sarcoma 180 cannot be restored in a resistant subline by increasing the uptake and external concentration of the drug.

We demonstrate the early effects (1 day) of Adriamycin (ADM) on proliferation-stimulated and quiescent sensitive, and ADM-resistant cells of the murine tumor sarcoma 180 (S 180). By investigating cell-cycle distribution and thymidine labeling, it can be shown that sensitive cells are strongly affected by the drug, even in a proliferationarrested state. A remarkable but slow DNA synthesis is the prominent effect of this drug treatment on sensitive cells, even under nonstimulating conditions. In resistant cells, neither an increase in concentration nor a variation in drug uptake can induce effects that could be compared with those observed in the sensitive line. From these results we conclude that the early effects of ADM are not modulated by drug uptake.

Animals↗
PubMed1989

Detection of P-glycoprotein in human leukemias using monoclonal antibodies.

Overexpression of a Mr 170,000 membrane glycoprotein (P-glycoprotein) is consistently associated with multidrug resistance in cell lines. Two monoclonal antibodies (Mab) against P-glycoprotein (265/F4 and C 219) were used to examine tumour samples from patients with leukemias for evidence of P-glycoprotein overexpression. High levels of P-glycoprotein (greater than 5% positive cells) were detected with both antibodies in samples from 3 out of 18 patients suggesting that a multidrug resistant phenotype may also occur in human leukemias.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Induced multidrug resistance in murine leukemia L1210 and associated changes in a surface-membrane glycoprotein.

The aim of this study was to find out whether only resistant cells of the "multidrug-resistant" phenotype show the described changes of plasma membrane glycoprotein (170 kDa) or whether resistant cells that do not express this phenotype reveal corresponding results. Doxorubicin-resistant (L1210dox) and daunorubicin-resistant L1210 ascites tumor cells (L1210dnr) (multidrug-resistant tumor cells) were therefore compared with cytosine-arabino-side-resistant (L1210AraC) and cyclophosphamide-resistant L1210 ascites tumor cells (L1210ctx) (not multi-drug-resistant tumor cells). The resistant cell lines were generated in vivo in tumor-bearing mice and the resistance to cytostatic agents was evaluated in vivo and in vitro. Using the accumulation assay with rhodamine-123, the multidrug resistance can be detected. In order to determine alterations in the plasma membranes we used the monoclonal antibodies 265/F4 and C219, which were prepared against the membrane glycoprotein P170 (170 kDa) in colchicin-resistant Chinese hamster ovary cells. The results demonstrate that L1210dox and L1210dnr tumor cells show an intense immunostaining by the streptavidin/biotinylated-peroxidase-complex method and by the streptavidin/biotin/phycoerythrin immunofluorescence method. In contrast no specific immunostaining was observed in parental (sensitive) and L1210AraC or L1210ctx tumor lines. The results were confirmed by immunoblotting. To determine whether multidrug-resistant DNA sequences were expressed in the multidrug-resistant tumor cells, Northern blots with RNA od sensitive and resistant cells were performed using the clone pcDR1.5. Elevated RNA levels were detected only in resistant cells with the multidrug-resistant phenotype. Thus, the results of this study demonstrate that only resistant cells with the multidrug-resistant phenotype show an increased expression of the membrane 170-kDa glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Detection of drug resistance in human ovarian carcinoma.

Drug-resistant cancer cells with the multidrug-resistance phenotype show overexpression of P-glycoprotein, and we therefore tested carcinoma tissue from five patients with stage III or IV ovarian cancer for P-glycoprotein using 265/F4 and C 219 monoclonal antibodies, prepared against membrane glycoproteins in colchicine-resistant CHO cells. Using immunofluorescence and immunoblotting techniques, one of the tumors showed a positive reaction. Using the pcDR 1.5 clone we found that the same cancer tissue had elevated expression of the genes responsible for multidrug resistance. The demonstration of elevated P-glycoprotein in ovarian carcinomas indicates that P-glycoprotein overexpression is not limited to experimental tumor models.

Carcinoma↗
PubMed1989

Flow-cytometric prognostic factors for the survival of patients with ovarian carcinoma: a 5-year follow-up study.

Fresh surgical specimens of 37 patients with previously untreated ovarian carcinomas were investigated by means of flow cytometry. The aim of the study was to look for cellular prognostic factors, in addition to the well-known clinical prognostic factors, of survival time for these patients. All patients underwent chemotherapy after surgery, and all patients had a minimum of 5 years of follow-up. Patients with diploid or near-diploid tumors (DNA index less than or equal to 1.25) survived significantly longer than those with aneuploid tumors (DNA index greater than 1.25, P = 0.02). Patients whose tumors showed a high proportion of SG2M phase cells (greater than 17%) or a low proportion of G0/G1 phase cells had shorter survival times than those with tumors with a low proportion of SG2M phase tumor cells (less than or equal to 17%, P = 0.01) or a high proportion of G0/G1 phase tumor cells. There is no significant relationship between cytometric data and stage. Different surgical procedures, cytostatic treatment, histological tumor type, and differentiation had no significant effects on the survival time of patients in this study. Thus, the data from this study demonstrate strong cytometric prognostic factors of the survival of patients with ovarian carcinomas.

Adult↗
PubMed1989

Detection of the multidrug resistant phenotype in human tumours by monoclonal antibodies and the streptavidin-biotinylated phycoerythrin complex method.

The aim of this study was to find out whether the membrane glycoprotein P-170 can be detected in human tumours with both acquired and intrinsic resistance to chemotherapeutic agents using monoclonal antibodies (265/F4 and C219) and the streptavidin-biotinylated phycoerythrin complex method. Pretreated leukaemia cells and untreated lung and ovarian carcinomas were analysed. Two plasmacytomas and one leukaemia expressed high levels of P-glycoprotein, whereas two leukaemias showed moderate, and three leukaemias no expression of this protein. The intrinsic resistance was analysed with a panel of four human epidermoid lung cancer xenografts grown in nude mice. The expression of P-glycoprotein could be correlated with the degree of resistance. In addition, one out of five ovarian carcinomas revealed a high level of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

P-glycoprotein expression in treated and untreated human breast cancer.

The expression of P-glycoprotein in primary and recurrent human breast cancer was investigated by means of immunohistochemistry, using a monoclonal antibody (C219) and the streptavidin-biotin-peroxidase method. Twelve patients received no chemotherapeutic treatment. The other 11 patients were treated with chemotherapy, and all developed clinical resistance to it. No or only minimal reactivity was found in specimens coming from the untreated patients (12 cases) or from patients treated with substances not involved in the multidrug resistance phenomenon (four cases). In contrast, three out of seven tumours from patients treated with multidrug resistance related substances showed clear reactivity (positive staining in more than 20% of the tumour cells). In one of these cases, where specimens of the tumour could be studied before and after treatment, an association between the latter and expression of P-glycoprotein was suggested. Finally, this marked expression of P-glycoprotein only took place in tumours treated over a longer space of time (five courses or more of multidrug resistance related chemotherapy).

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Radiosensitivity of drug-resistant human tumour xenografts.

The radiosensitivity of three drug-resistant sublines of a human epidermoid lung carcinoma growing as xenografts in nude mice was investigated. Drug resistance to vincristine, actinomycin D and cisplatin was developed in vivo by repeated drug treatment. It was found that all three drug-resistant tumour lines were not cross-resistant to irradiation.

Animals↗
PubMed1989

Response of the R3327-AT1 Dunning prostate tumor to fast neutrons and cobalt-60.

Reasons why neutron therapy may be successful include tumor's rate of proliferation, state of oxygenation at time of onset of radiation and the efficacy of reoxygenation during therapy, inherent radioresistance and repair capacity. In an effort to better understand the action of neutrons on tumor tissues we started studies with the Dunning rat prostate tumor system. This tumor system has sublines available with differing histologies, doubling times, hormone dependency and metastatic potential. The present report pertains to anaplastic carcinoma R3327-AT1 subline. The tumors transplanted into the distal thigh received single doses of 8 through 15 Gy of 14.5 MeV neutrons and 18 through 30 Gy Co-60 after they had reached a volume of about 450 mm3. The tumors exhibited a dose dependent retardation in further growth. An RBE of 3 was estimated by comparing the time required for a tumor to reach a normalized value of five times the initial treatment volume. We plan to extend our studies to include a slower growing well differentiated subline.

Animals↗
PubMed1989

[Morphologic and tumor-marker studies of human planocellular carcinoma of the bronchi in xenografts].

Authors have studied the morphology of 10 human planocellular bronchus carcinoma xenografts parallel with that of the donor tumour. The expression of cytokeratin, epithelial membrane antigen and carcinoembryonic tumour markers was also studied and compared. The histological structure and marker expression of xenografts did not change as compared to the donor tissue. Tumour cells were characterized by cytokeratin rather than epithelial membrane antigen. Carcinoembryonic antigen positivity occurred mainly in well-differentiated tumours. The cellular heterogeneity of human planocellular bronchus carcinomas was found to occur also in xenograft tumours.

Antibodies, Monoclonal↗
PubMed1989

[Demonstration of independent cellular prognostic factors in squamous cell carcinoma of the lung].

The aim of this investigation was to find out whether a histopathologically homogeneous group of patients (similar in histology, grade, operation, and therapy) could be divided with respect to survival by determining cellular tumor factors. Therefore out a group of 100 patients 46 patients with previously untreated epidermoid lung carcinomas were selected. From these patients fresh surgical specimens of tumors were investigated by means of flow cytometry and the obtained data were correlated with five years survival. Patients with aneuploid tumors had significantly shorter survival times than did those with diploid tumors (p = 0.02). Seven of eleven patients with diploid tumors survived five years or more, whereas 25 of 35 patients with aneuploid tumors died within this period. Patients having tumors with a high proportion of G0/G1-phase cells survived significantly longer (p = 0.04) than patients having tumors with a lower proportion of G0/G1-phase cells. Within five years half of the patients with a high proportion of G0/G1-phase cells survived in contrast to 10% of patients in the other group. These data demonstrate that in addition to the well known clinical and histological factors independent cytometric prognostic factors in epidermoid carcinoma of the lung exist.

Aneuploidy↗
PubMed1989

Acquired drug resistance in human lung carcinoma xenografts.

The development of resistance to vincristine and dactinomycin has been investigated in a human epidermoid lung xenograft line grown in nude mice. With 1 mg/kg BW vincristine and 0.5 mg/kg BW dactinomycin per passage, resistance of the solid tumors was visible already at the second transplantation. The vincristine-resistant subline showed cross-resistance to dactinomycin and doxorubicin, and the dactinomycin-resistant subline only to vincristine. To determine whether multidrug resistance genes were overexpressed in the resistant sublines, slot blots were performed using the cDNA probe pcDR 1.5. Slightly elevated RNA levels could be detected in the vincristine-resistant subline and in the dactinomycin-resistant subline.

Animals↗
PubMed1988

Synthesis and cytotoxic effects of hydroxymethyl-3-pyridyl- and 2-chloro-5-pyridyltriazene derivatives.

3-Hydroxymethyl-3-methyl-1-(3-pyridyl)-triazene (III) and 3-hydroxymethyl-3-methyl-1-(2-chloro-5-pyridyl)-triazene (VI) were synthesized and their cytotoxic effects towards S180 cells compared with those of the corresponding dimethyltriazene and monomethyltriazene derivatives. The hydroxy-methyltriazenes were one to two orders of magnitude more inhibitory than the corresponding dimethyl analogs, as assessed by cell growth, colony forming and macromolecular synthesis assays. Comparable effects were observed with the related monomethyl triazenes indicating that the activity of (III) and (VI) could result, at least in part, from release of monomethyl derivatives. The corresponding dimethyltriazenes were much less toxic to S180 cells and exerted only an unspecific cytotoxic activity at the maximal attainable dose (5 X 10(-3) M). The cytotoxic activities of the tested triazenes were correlated with their chemical half-lives under near physiological conditions (pH 7.5).

Animals↗
PubMed1988

Five-year follow-up study of independent clinical and flow cytometric prognostic factors for the survival of patients with non-small cell lung carcinoma.

Fresh surgical specimens of tumors of 187 patients with previously untreated non-small cell lung carcinomas were investigated by means of flow cytometry. The aim of the study was to look for cellular prognostic indicators for survival times of these patients in addition to the well-known clinical prognostic factors. All patients had a minimum of 5 years follow-up. Patients with aneuploid tumors had significantly shorter survival times than did those with diploid tumors (P less than or equal to 0.001). 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 who were classified as Stage III (P less than or equal to 0.01). These data indicate that DNA ploidy is a strong and independent prognostic factor in patients with non-small cell lung carcinoma. Patients having tumors with a high proliferative activity died significantly (P less than 0.05) earlier than patients having tumors with lower proliferative activity. As with tumor ploidy, survival time in patients with high or low proliferative tumor activities was independent of whether the patients had T3-tumors, metastases, or were in Stage III. Univariate and multivariate analyses of the data in this study demonstrate two groups of independent prognostic factors for the survival of patients with non-small cell lung carcinoma: a group of clinical factors and a group of flow cytometric factors.

Adult↗
PubMed1988

DNA and S-phase distribution and incidence of metastasis in human primary lung carcinoma.

The aim of the study was to investigate the relationship between DNA and S-phase distribution in primary non-small-cell lung carcinomas with the incidence of metastasis. Patients with non-small-cell lung carcinomas were divided into two groups depending on whether at time of surgery there were metastases or not, and these groups were correlated with the data obtained by flow cytometry or autoradiography. As expected from other studies, survival time was significantly longer for those patients without metastases at time of surgery (P = .0002) and the incidence of metastasis was significantly higher when the primary tumor was greater than or equal to 70 cm3 (P = .026). In this study, a total of 185 fresh specimens of lung carcinomas were investigated by flow cytometry. Patients with aneuploid tumors had a higher tendency to have metastases (P = .016). Patients with tumors with a higher proportion of S-phase cells measured by either flow cytometry or autoradiography demonstrated significant increase in the formation of metastases (P = .02 and P = .05). We feel that these results warrant further investigation with other primary tumors. A comparison of primary tumors that are known to rapidly metastasize vs. those that either slowly or rarely metastasize may prove to yield valuable insight into the important factors associated with metastatic potential.

Carcinoma, Non-Small-Cell Lung↗