Biomedical subjects

G H Mickisch

Publications and source records attributed to G H Mickisch.

40 records · Page 3Linked to original sources

PubMed1990

Effects of calcium antagonists in multidrug resistant primary human renal cell carcinomas.

Human renal cell carcinomas display a characteristically high degree of intrinsic chemoresistance to a multitude of chemotherapeutic agents. It was suggested previously, that P-170 glycoprotein contributes to this phenomenon in renal cell carcinoma indicated by elevated MDR-1 gene mRNA levels and by the expression of this specific resistance characteristic. The P-170-related efflux mechanism can be inactivated by certain calcium antagonists. P-170 was traced immunohistochemically using monoclonal antibody C 219. Concomitantly, we studied the enhancement of vinblastine cytotoxicity with 4 major classes of calcium-blocking agents in a microculture tetrazolium assay. Seven different calcium antagonists were selected: verapamil (VPM, racemic form), its R-stereoisomer (R-VPM), diltiazem, flunarizine, nifedipine, and its derivatives nimodipine and nitrendipine. Verapamil or R-verapamil causes a significant decrease of viable tumor cells as compared to vinblastine alone (P less than 0.001). Similar effects were found with diltiazem, nifedipine, and its derivatives reaching approximately 70% of the VPM/R-VPM activity. Flunarizine showed only minor enhancement of cytotoxicity. P-170 expression was demonstrated in 18 of 32 tumors, and a relation to chemoresistance was evident. None of the chemoresponders, but 18 of 25 (72%) of the highly resistant tumors, revealed this resistance factor. It was concluded that certain calcium antagonists in combination with chemotherapy may well offer therapeutic options in renal cell carcinoma as they apparently inactivate the underlying mechanism conferring resistance. The new stereoisomer R-VPM, in particular, may be used in clinical trials since it combines strong enhancement of vinblastine drug responsiveness with a 10-fold lower cardiovascular activity as compared to racemic VPM, thus allowing higher concentrations to be applied.

Calcium↗

PubMed1990

Mechanisms and modulation of multidrug resistance in primary human renal cell carcinoma.

Human renal cell carcinomas show a high degree of intrinsic multidrug resistance. In experimental cell lines, the membrane bound P-170 glycoprotein and the glutathione redox cycle seem to contribute to this phenomenon. P-170 may be inactivated by calcium antagonists; the glutathione redox cycle by buthionine sulfoximine. We studied the resistance patterns of 35 human renal cell carcinomas against vinblastine, doxorubicin and carboplatinum in a tetrazolium-based microculture assay. Concomitantly, P-170 expression was traced immunohistochemically using moab C219 and the glutathione content was determined enzymatically. Reversal of multidrug resistance was examined by applying the R-stereoisomer of verapamil and/or by addition of buthionine sulfoximine. A high degree of chemoresistance was seen in 27 tumors against vinblastine, in 30 tumors against doxorubicin and in 31 tumors against carboplatinum. Chemoresponse was found in eight, five or four cases respectively. P-170 was detected in 70% of highly vinblastine resistant and in 63% of highly doxorubicin resistant tumors, but in none of the less resistant cases. Resistance against carboplatinum and doxorubicin was significantly associated with elevated glutathione levels as compared to less resistant renal cell carcinomas. R-verapamil lead to a strong reversal of vinblastine resistance and to a distinct circumvention of doxorubicin resistance, but revealed no effect in carboplatinum resistance. Buthionine sulfoximine overcame carboplatinum resistance and modified doxorubicin resistance, but had no influence on vinblastine resistance. The combined application of R-verapamil and buthionine sulfoximine reversed doxorubicin resistance but did not act synergistically in vinblastine or carboplatinum resistance. Both mechanisms, P-170 and glutathione, occurred independently of each other and may well explain multidrug resistance of human renal cell carcinomas.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1986

Surgical resection and adjuvant chemotherapy for small cell carcinoma.

Poor long-term results following the surgical management of small cell carcinoma have contributed to the opinion that small cell carcinoma is a non-surgical disease; polychemotherapy is generally given preference. As nowadays adequate therapy (chemotherapy) achieves control of local tumor growth as well as of extended metastases, surgical resections should be discussed from a different viewpoint: "Does surgery profit from modern chemotherapy?" In our clinic, 1332 patients have been operated on for bronchogenic carcinoma from 1973 to 1983: 170 (12.8%) suffered from small cell carcinoma. The indications for surgery were either non-histologically classified tumors (e.g. peripheral coin lesions) or small cell carcinomas stage I, and only in rare cases for palliative reasons. Lobectomy, including bronchoplastic and arterioplastic resections (n = 108), was the most common procedure. The postoperative mortality was 15%, the average survival 341 days, the latter having improved significantly since 1979 when a postoperative polychemotherapy (ACO) was instigated. Recent results of surgical resection after primary chemotherapy are encouraging. Nevertheless, this new concept is reserved for the few cases of strictly limited disease and must be controlled by future studies.

Adolescent↗

PubMedDate not supplied

Inhibition of apoptotic proteins causes multidrug resistance in renal carcinoma cells.

Renal Cell Carcinomas (RCCs) exhibit strong resistance to the most chemotherapeutic treatments probably due to the expression of various multidrug resistance (MDR) genes. Overexpression of P-glycoprotein (Pgp) is established as one such factor, but other mechanisms such as at-MDR, characterized by attenuated DNA-topoisomerase II (topoII) activity, may be functional as well. In addition, regulating proteins involved in apoptosis can exhibit multidrug resistant features. However, prevention of apoptosis as a mechanism of MDR has not yet been assessed in RCC, nor has the cytotoxicity of a variety of chemotherapeutic agents known to trigger apoptotic or necrotic cell death been tested in RCC in a systematic fashion. Using immunohistochemistry and Western blotting, Bcl-2 and Bax expression was determined in a panel of multidrug resistant RCC lines featuring Pgp and/or at-MDR. The results were related to apoptotic activity and kind of cell death in these cell lines, demonstrated by incubation with Hoechst 33342 and propidium iodide after treatment with various cytotoxic agents and quantitated by MTT. In the drug resistant sublines, some decreased Bax and strongly increased Bcl-2 expression was seen by immunohistochemistry indicating prevention of apoptosis as a distinct feature of MDR in RCC. This was confirmed by Western blotting. Sublines revealed significant resistance for all drugs, except for CC-313 and DiMIQ. However, these drugs induced necrotic cell death, in contrast to all other drugs tested, which induced apoptotic cell death. We conclude that, in chemoselected RCC sublines, multidrug resistance appears to be functional due to inhibition of apoptosis, apart from the MDR1 and at-MDR resistance mechanisms. CC-313 and DiMIQ are very potent cytotoxic agents in RCC, probably because they do not kill by induction of apoptosis.

Amsacrine↗