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M Volm

Publications and source records attributed to M Volm.

At least 127 records · Page 7Linked to original sources
PubMed1988

Human tumor xenografts as model for drug testing.

This paper reviews the history of xenografts, the endpoints commonly used to evaluate response and chemotherapeutic results obtained with serially maintained human tumor xenografts from different laboratories, and discusses the potential clinical relevance of the heterotransplant model for cancer chemotherapy. Specifically, an attempt is made to correlate the published xenograft data with the clinical data. Drug testing with different types of xenotransplanted tumors has shown that the response of xenografts obtained in immune-deficient animals is comparable to that in clinical practice. In addition, xenografts of a particular tumor type are able to identify agents of known clinical activity against that disease.

Animals↗
PubMed1988

Development of drug resistance in a human epidermoid lung carcinoma xenograft line.

The development of resistance to vincristine, actinomycin D and cisplatin has been examined in a human epidermoid lung carcinoma xenograft line (HXL 55) growing in nude mice. Treatment of HXL 55 with 1 mg kg-1 vincristine or 0.5 mg kg-1 actinomycin D once in each in vivo passage resulted in a rapid reduction in tumour responsiveness to these drugs. A partial resistance was already acquired at the 2nd transplant generation. In contrast, a gradual decrease in therapeutic response was observed with 10 mg kg-1 cisplatin. Irradiation with a local dose of 10 Gy induced no resistance. The three induced drug-resistant sublines were characterized in terms of the time course of development of resistance, the degree of induced resistance, cross-resistance, growth rate and stability of the phenotype.

Animals↗
PubMed1988

Intrinsic drug resistance in a human lung carcinoma xenograft is associated with overexpression of multidrug-resistance DNA-sequences and of plasma membrane glycoproteins.

The purpose of this study was to examine whether multidrug resistance can be detected in human lung tumors not previously treated with chemotherapy. Therefore, the intrinsic sensitivity or resistance of 8 human epidermoid lung cancer xenografts grown in nude mice has been examined. The tumor lines responded differently to vincristine and the other cytostatic agents. When the effects of vincristine on the 8 tumor lines are correlated with the effect of dactinomycin (actinomycin D), a close relationship could be found (r = 0.96). These results demonstrate that xenografts derived from human lung tumors not previously treated with chemotherapy exhibited a similar pattern of cross-resistance as is observed in sublines of murine and human tumors which were resistant to various drugs following repeated exposure of the cells to a sublethal concentration of these drugs. The resistant lung tumor HXL 54 also shows an overexpression of the P170-membrane glycoprotein (detected by Mab 265/F4). To determine whether multidrug genes were expressed in resistant lung tumors, slot blots and Northern blots were performed using the probes pDR 7.8 and pcDR 1.5. The level of expression can be correlated with the degree of drug resistance.

Animals↗
PubMed1988

Rapid detection assays for multidrug resistance.

In attempts to develop simple and rapid assays for detection of multidrug resistance (MDR) doxorubicin-resistant S180 (S180DOX), colchicine-resistant CHO (CHOCOL) and cytarabine (cytosine-arabinoside)-resistant L1210 cell lines (L1210AraC) were investigated. S180DOX and CHOCOL cells express the MDR-phenotype while L1210AraC does not. Using a previously described short-term assay firstly, inhibition of incorporation of radioactive nucleic acid precursors into tumour cells after addition of doxorubicin was measured. Secondly, the accumulation of the fluorescent dye rhodamine 123 (R123) in the different cell lines were analyzed. It could be observed that the resistant S180DOX and CHOCOL cells needed significantly more time to accumulate R123 than their sensitive parental cell lines or L1210AraC cells. Therefore, both assays are adequate tools for the rapid detection of MDR.

Animals↗
PubMed1987

Occurrence of a multidrug-resistant phenotype in human lung xenografts.

The intrinsic sensitivity of a panel of 8 human epidermoid lung cancer xenografts to vincristine and actinomycin D has been examined and the cross-resistance patterns of the most vincristine-resistant and vincristine-sensitive tumour line were tested to a variety of other drugs, including radiation. The results demonstrate that xenograft lines derived from human lung tumours not previously treated with chemotherapy exhibit a similar general pattern of cross-resistance to the drugs vincristine, actinomycin D and adriamycin as is observed in human cell lines and in animal models selected for resistance to these drugs. It is also shown that intrinsic resistance to vincristine can be partially overcome by verapamil. This may indicate a potential role of this substance in circumventing clinically observed drug resistance.

Animals↗
PubMed1987

[Prognostic significance of flow cytophotometric studies in ovarian cancer].

Prognostic significance of DNA content and of distribution of cell cycle phases in ovarian carcinomas (stage III and IV) were investigated using flow cytometry. From 37 tumors 15 had DNA indices less than 2.5 and 22 had DNA indices greater than or equal to 2.5 (diploid = 2). Patients with diploid or near diploid tumors had significantly longer survival times than those with aneuploid tumors (DNA indices greater than 2.5) (log-rank test, p = 0.009, rank-sum test, p = 0.011). Patients whose tumors showed a high proportion of S/G2/M-phase cells (greater than 17%) had shorter survival times than those with tumors with a lower proportion of S/G2/M-phase cells (log-rank test p = 0.009, rank-sum test p = 0.022). The median length of follow-up of the patients was 4 years. Thus, our experiments have shown that measurements of DNA ploidy and proliferative activity using flow cytometry are important prognostic indicators for patients with ovarian carcinomas. In the future these factors might play an important role for the prognosis of patients with ovarian carcinomas. In addition, there exists a tendency for patients with in vitro resistant tumors to die earlier than those with sensitive tumors, but these results were not significant (log-rank test, p = 0.16; rank-sum test, p = 0.059).

Adult↗
PubMed1987

Flow cytometry as a tool for the prognostic assessment of patients with lung and ovarian carcinomas.

In two cooperative studies surgical specimens of 187 tumors of patients with non-small cell lung carcinomas (NSCLC) and 37 tumors of patients with ovarian carcinomas (OC) were investigated by means of flow cytometry (ICP-22). From NSCLC30 cases were classified as tumors with DNA diploidy, 119 as tumors with DNA aneuploidy containing one abnormal DNA stemline, and 38 as tumors with DNA aneuploidy containing more than one abnormal DNA stemline. Seven tumors of patients with OC were classified as tumors with DNA diploidy, and 31 as tumors with DNA aneuploidy (three cases had more than one abnormal DNA stemline). The DNA index values of NSCLC range from 0.7 to 4.5 and the values of OC from 0.8 to 2.7 (DNA diploid = 1). A relationship between DNA content and distribution of the cell cycle phases was observed. The results of DNA content analysis have prognostic importance with regard to the length of survival time. Patients with aneuploid and high proliferative tumors had shorter survival times than did those with diploid or near diploid tumors and tumors with low proliferative activity.

Aged↗
PubMed1987

Detection of murine S180 cells expressing a multidrug resistance phenotype using different in vitro test systems and a monoclonal antibody.

Doxorubicin (adriamycin) preconditioned S180 cells were more resistant to doxorubicin. The resistance was detected by three different methods (short-term test, colony assay, tissue culture assay). The doxorubicin-resistant S180 cells express the pleitrop drug resistance phenotype. There exists a multidrug resistance to doxorubicin, dactinomycin (actinomycin D), vincristine and colchicine. In addition, collateral sensitivity was found to fluorouracil (5-fluorouracil) and methotrexate. This multidrug phenotype is in accordance with the pleiotropic phenotype of colchicine-resistant CHO cells. Resistant S180 cells express a glycoprotein of Mr 170 kd determined by indirect immunofluorescence using a monoclonal antibody (Mab 265/F4) to the P-glycoprotein of colchicine-resistant CHO-cells. The P-glycoprotein could be an important prognostic factors for tumors with multidrug resistance.

Animals↗
PubMed1986

Decreased autolysis of dead cells in adriamycin-resistant lines of the sarcoma 180 of mouse.

Adriamycin-resistant cell lines of the sarcoma 180 of mouse reveal, besides the known resistance mechanism, a decrease in cellular autolysis compared with the original line. This decrease has been demonstrated by comparative analysis of cell-free supernatants isolated from 7-day-old sensitive and resistant ascites tumors in mice. In order to demonstrate these changes we isolated and quantified the DNA, detecting higher amounts within the supernatants of resistant lines. Furthermore, unspecific DNA-cleaving activity within raw homogenates of the cells is substantially lower in the resistant lines. Residual parts of chromatin may trap the drug and in this way lower its effective concentration. However, the results may also reflect changes in enzymatic complement playing a hitherto unknown role within living cells.

Animals↗
PubMed1985

Prognostic significance of DNA patterns and resistance-predictive tests in non-small cell lung carcinoma.

In a cooperative study, 240 surgical specimens of patients with non-small cell lung carcinomas (NSCLC) were investigated by means of flow cytometry, xenotransplantation to athymic mice and, an in vitro short-term test for predicting resistance. Aneuploidy was found in 83% of the tumors, and 20% showed more than one aneuploid DNA stemline. Patients with both aneuploid tumors and tumors with more than one DNA stemline had a significantly shorter survival rate than those with only diploid or only one DNA stemline. Patients whose tumors showed a low G0/G1-cell proportion or a high proliferation pool (S and G2/M-cell proportion) died earlier. A relationship could not be discerned between growth of tumors in nude mice or establishment of cell lines and the prognosis for the patients. Patients with in vitro-resistant tumors died earlier under chemotherapy than those with in vitro-sensitive tumors. Patients treated by radiation survived longer if the tumors were resistant in vitro. Thus, DNA patterns and in vitro short-term tests for predicting resistance represent useful tools for prognostic evaluation of patients with NSCLC.

Adult↗
PubMed1985

DNA distribution in non-small-cell lung carcinomas and its relationship to clinical behavior.

A study of 187 surgical specimens of tumors of patients with non-small-cell lung carcinomas was carried out by means of flow cytometry. Eighty-four percent of the tumors were classified as tumors with abnormal DNA stemlines (DNA aneuploidy). Patients with tumors demonstrating DNA aneuploidy had significantly shorter survival times than those with tumors demonstrating DNA diploidy (p = .009). Cell cycle analysis was possible in 122 tumors. Patients whose tumors had 0-8% S-phase cells died later than patients whose tumors had 9-16% S-phase cells (p = .018). In addition, patients with tumors with a low fraction of labeled S-phase cells (autoradiography) had a better prognosis than patients with tumors with a high proportion of labeled S-phase cells (p = .041).

Adenocarcinoma↗
PubMed1985

Anthracycline resistance and consequences of the in situ-in vitro transfer.

Adriamycin-resistant and normal cells of the sarcoma 180 of the mouse undergo qualitatively different deflections from the in situ state when prepared for an experiment. Resistant cells perform a fast reactive decline in the proliferative activity. They are capable of quiescence as defined by the time needed for the induction of the proliferation. Sensitive cells seem to be unable to quiesce and are only slowed down. These facts must be taken into account in interpretation of similar results. Differences in experiments need not necessarily imply differences in situ. Such in vitro appearing differences between sensitive and adriamycin-resistant cells of the murine sarcoma 180 include the retention of the mitochondria-specific stain rhodamine 123 and the uptake of anthracyclines, both being reduced in resistant cells. After labeling sensitive cells with thymidine in vivo and sorting them according to their rhodamine 123-derived fluorescence, the label was only found in the major, highly fluorescing fraction. A small low-fluorescing fraction remained unlabeled. We were able to demonstrate similar results with labeled anthracyclines applied to both the sensitive and the resistant cells in a short period between the removal of the cells from the ascites and the cell sorting. The adriamycin resistance seems to be joined with the ability of the cells to reduce their proliferative activity following changes to unfavorable conditions in vitro. Quiescent cells of the resistant line demonstrate the "anthracycline pump." Substances which are known to increase the sensitivity of anthracycline-resistant cells (TWEEN, verapamil) also shift the cells from low to high rhodamine 123-fluorescence.

Animals↗
PubMed1985

Sequential methotrexate (MTX) and 5-fluorouracil (FU) in human tumor xenografts.

Human and animal tumor-lines heterotransplanted in nude mice were treated with MTX and FU sequentially. In order to investigate the relationship between tumor response and drug toxicity sequence, time and dose of both MTX and FU were varied. Pretreatment with MTX followed by FU with intervals of 3 or 24 h produced superior therapeutic results when compared to single administration of MTX or FU, simultaneous treatment, or the reverse sequence. In the MTX followed by FU regimen, dose reduction of either MTX or FU tended to decrease the anti-tumor effect. To investigate the toxic effects of different regimens, tumor-free nude mice were treated with MTX and FU the same way as the tumor-bearing animals. In this case, toxicity (weight loss, leukopenia) was more pronounced in those schedules with the best therapeutic results. However, toxicity appears to be more clearly related to the applied FU-dose.

Animals↗
PubMed1985

Growth of human bronchial carcinomas in nude mice.

Two hundred and thirteen lung tumours of primary site and 42 metastases were heterotransplanted into nude mice with an overall success rate of 44%. There were differences in success between the histological types. Squamous cell and adenocarcinoma had the highest success rate (51% and 43%, respectively) whereas large cell and small cell carcinoma had a lower success rate (38% for both). The average volume doubling times in the first passage in nude mice ranged from 8.2 in large cell carcinomas to 18.9 days in adenocarcinomas. In subsequent passages an increase in growth rate was found, the overall average doubling time falling from 14.5 days in the first passage to 7.1 days in the second passage. In a study with 171 non-small cell lung carcinomas (NSCLC), the growth data in nude mice were correlated with the clinical data of the corresponding patients. A relationship between the growth parameters in nude mice and prognosis of patients could not be found.

Adenocarcinoma↗
PubMed1985

Influence of hormone therapy on human lung tumors transplanted into nude mice.

Specific estrogen, progesterone, androgen and glucocorticoid receptors were determined in 8 lung tumor lines transplanted into athymic nude mice. It was found that the receptor content for estrogen, progesterone or androgen was very low for all tumor lines tested, whereas the glucocorticoid receptor content was high in all cases except 1. The growth inhibition of lung carcinomas on nude mice by glucocorticoid or antiglucocorticoid treatment suggests that lung cancer may also be influenced by hormonal therapy.

Animals↗