Biomedical subjects

S S Larsen

Publications and source records attributed to S S Larsen.

At least 19 recordsLinked to original sources

PubMed1999

[Neoadjuvant chemotherapy in non-small-cell lung cancer].

Over the past 10 years, several studies of neoadjuvant chemotherapy for stage III Non Small Cell Lung Cancer (NSCLC) have been conducted. In eight Phase II studies, response rates of approximately 65% and resectability rates of approximately 50% have been achieved, with acceptable side effects. Two randomized trials with a total of 120 patients with stage IIIA cancer have been carried out to compare the effect of neoadjuvant chemotherapy plus surgery versus surgery alone. The trials were terminated early when interim analysis showed significantly increased survival in groups that received neoadjuvant chemotherapy. The incidences of treatment-related death did not differ significantly between the groups. Neoadjuvant chemotherapy for patients in stage III NSCLC is feasible and might prolong survival. However, the results of larger randomized trials must be awaited before firm general recommendations can be made.

Carcinoma, Non-Small-Cell Lung↗

PubMed1999

Acquired antiestrogen resistance in MCF-7 human breast cancer sublines is not accomplished by altered expression of receptors in the ErbB-family.

Development of acquired resistance against antiestrogen treatment is a serious problem in human breast cancer, and knowledge of alterations resulting in resistance is important for selection of further treatment. To mimic the clinical situation we have established a series of MCF-7 human breast cancer cell lines by long term treatment with the antiestrogens tamoxifen, ICI 164,384, and ICI 182,780. Common for these cell lines is a decreased expression of the estrogen receptor alpha (ER alpha). In human breast cancer, lack of response to endocrine therapy is often associated with decreased expression of the estrogen receptor and increased expression of epidermal growth factor receptor (EGFR) and/or HER-2/neu (ErbB-2). Our antiestrogen resistant cell lines did not express altered levels of EGFR, HER-2/neu, ErbB-3, or ErbB-4. Estrogen and antiestrogen regulation of HER-2/neu expression was essentially similar in parent and resistant MCF-7 cells. Treatment with antibodies to HER-2/neu (Herceptin) did not affect growth of MCF-7 cells or resistant cells, indicating that in this in vitro model system, acquired antiestrogen resistance does not emerge from activation of the HER-2/neu signaling pathway. In MCF-7 cells transfected with HER-2/neu and/or ErbB-3, overexpression alone did not result in resistance. However, addition of heregulinl-beta1 abolished the inhibitory activity of ICI 182,780 on both vector and HER-2/neu/ErbB-3 transfected MCF-7 cells, demonstrating that activation of the HER-2/neu receptor signaling pathway can override the growth inhibitory effect of ICI 182,780.

Blotting, Northern↗

PubMed1999

Development of a model for measurement of adhesion strength of fibrin sealant to human tissue.

It is crucial for the surgeon to know the physical properties of a surgical sealant. Current test methods of fibrin sealant involving animal testing or in vitro testing of sealant using artificial substrates have little clinical relevance. Most of these test methods also lack accuracy and reproducibility. A new model was developed for testing strength and in vitro adhesion of fibrin sealant to vital human tissue using fresh vein leftover from coronary artery bypass grafting. The vein leftover was cut into samples and fastened in a tensiometer linked to a computer. Patient-derived fibrin sealant (0.1 ml) was applied to the tissue, and the surfaces of the tissue samples were held together for 5 min, and then automatically pulled apart by the tensiometer. Data were generated in a load cell and recorded and analysed by the computer. The reproducibility for the adhesion strength was 6.6%, adhesion energy 9.8%, and elongation at break 8.4%. The method has been considered ethical and has good reproducibility. The method can be used for standardised measurements and comparison of different types of fibrin sealant without the sacrifice of animals.

Adhesiveness↗

PubMed1997

Resistance of human breast-cancer cells to the pure steroidal anti-estrogen ICI 182,780 is not associated with a general loss of estrogen-receptor expression or lack of estrogen responsiveness.

To elucidate the mechanisms responsible for the development of anti-estrogen resistance, we have cloned and established 3 stable ICI-182,780-resistant sub-lines, MCF-7/182R-1, MCF-7/182R-6 and MCF-7/182R-7 from the estrogen-receptor(ER)-positive and estrogen-responsive human breast-cancer MCF-7 cell line by long-term treatment with 10(-7) M ICI 182,780. The ICI-182,780-resistant MCF-7 sub-lines express ER, but compared with MCF-7 cells the level is significantly lower in all 3 sub-lines. In the MCF-7 cell line we find that ER expression is regulated by estrogen and anti-estrogens at the transcriptional and post-transcriptional level. This is in contrast to the ICI-182,780-resistant sub-lines, in which we find very little hormonal effects on the ER mRNA expression level. The resistant sub-lines also deviate from parent characteristics by the complete lack of expression of progesterone receptor even when grown in the presence of estradiol. All 3 resistant sub-lines have a lower basal expression of cathepsin-D mRNA comparable with the lower ER expression, but, in contrast, they have higher basal expression of the pS2 mRNA than the parent MCF-7 cell line. Although there are different basal expression levels of the pS2 and cathepsin-D genes, the resistant sub-lines behave like the parent MCF-7 cell line with respect to the hormonal regulation of both genes. The estrogen receptors in the resistant sub-lines have also maintained wild-type characteristics with respect to estrogen and anti-estrogen regulation of the estrogen-regulated proteins procathepsin D, alpha1-antitrypsin and a 42-kDa protein. The resistant cells require estrogen for growth in athymic nude mice. Our results clearly demonstrate that the ER in the resistant sub-lines have a normal function for most parameters investigated, supporting our earlier observation that only wild-type ER protein is expressed in these cells. The few observed differences in ER function between the parent MCF-7 cell line and the resistant sub-lines are not likely to be responsible for the ICI-182,780-resistant phenotype.

Animals↗

PubMed1997

Estrogen receptor messenger RNA splice variants are not involved in antiestrogen resistance in sublines of MCF-7 human breast cancer cells.

Development of resistance to tamoxifen is a serious problem in treatment of breast cancer patients. Although the mechanisms for development of resistance are unclear, an altered expression of alternatively spliced estrogen receptor (ER) mRNA has been suggested to be involved. We have looked for differential expression of ER splice variants lacking exon 2 (ERdeltaE2), exon 3 (ERdeltaE3), exon 4 (ERdeltaE4), exon 5 (ERdeltaE5), exon 7 (ERdeltaE7), and exons 4 and 7 (ERdeltaE4, 7) in the human breast cancer cell line MCF-7 and 10 ER-positive MCF-7 sublines resistant to the antiestrogens tamoxifen, ICI 164,384 or ICI 182,780. No major differences in the expression were demonstrated between MCF-7 cells and resistant cells, indicating that ER splice variants are not involved in antiestrogen resistance in this model system. Furthermore, despite a high mRNA level of some of the ER splice variants, no corresponding proteins could be detected using Western blot analysis.

Antineoplastic Agents, Hormonal↗

PubMed1995

Human breast cancer cell lines resistant to pure anti-estrogens are sensitive to tamoxifen treatment.

The pure steroidal anti-estrogens ICI 164,384 and ICI 182,780 are very potent growth inhibitors of the estrogen receptor-positive human breast cancer cell line MCF-7. However, long-term treatment of MCF-7 cells with 10(-7) M concentrations of these compounds results in selection of proliferating colonies of resistant cells. Our report describes 4 ICI 164,384- and 3 ICI 182,780-resistant MCF-7 sublines established after long-term treatment. Resistant sublines are estrogen receptor-positive, and all sublines have lost expression and estrogen inducibility of the progesterone receptor protein. Based on IC50 concentrations, all tested resistant sublines had a reduced sensitivity to pure anti-estrogens on the order of 100- to 1000-fold compared with parent MCF-7 cells. All resistant cell lines have survived propagation for more than 15 subcultivations in the presence of 10(-7) M pure anti-estrogen. The MCF-7/182R-6 subline has been tested for stability of resistance and appeared to be stably resistant after 13 weeks of propagation without the selective pressure of ICI 182,780. Cell lines resistant to the ICI 182,780 compound are cross-resistant to the ICI 164,384 compound and vice versa. However, the sublines resistant to pure antiestrogens are sensitive to tamoxifen. Our results show that although the pure steroidal anti-estrogens are very potent growth inhibitors, they do not circumvent development of resistance.

Animals↗

PubMed1988