Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Publication year range
1.
Urol Int ; 47(3): 118-25, 1991.
Article in English | MEDLINE | ID: mdl-1685271

ABSTRACT

In experimental cell lines and in some human tumors, calcium antagonists reversed multidrug resistance mediated by P-170 glycoprotein in vitro. So far, clinical trials have not been very rewarding as intrinsic cardiovascular activities of these compounds impeded sufficient dosage. Renal cell carcinomas are considered to be good models for the evaluation of this new therapeutic concept. In 35 primary human renal cell carcinomas, the potency of 7 different calcium antagonists in combination with vinblastine monotherapy was examined in a tetrazolium-based microculture assay (MTT test) in order to circumvent chemoresistance. Concomitantly, P-170 glycoprotein expression was traced immunohistochemically using moab C 219. Substances derived from piperazine (flunarizine) showed only minor effects in this respect. The calcium antagonists of the papaverine type such as verapamil etc. revealed the strongest reversal of chemoresistance. Derivatives of benzothiazepine (diltiazem) or of dihydropyridine (nifedipine etc.) acted similarly and reached about 70% of the verapamil activity. All calcium antagonists lead to a significant enhancement of vinblastine cytotoxicity. An obvious link of P-170 glycoprotein to vinblastine chemoresistance was demonstrated. This particular resistance characteristic was detected in 19 of 27 resistant cases, but in none of the tumors displaying a chemoresponse. In particular, the new stereoisomer R-verapamil, which showed strong reversal of chemoresistance but which exerts 10 times lower cardiovascular side effects than racemic verapamil, seems to be suitable for further evaluation with regard to the clinical application.


Subject(s)
Calcium Channel Blockers/pharmacology , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Membrane Glycoproteins/physiology , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Carcinoma, Renal Cell/chemistry , Carrier Proteins/physiology , Drug Resistance , Humans , Kidney Neoplasms/chemistry , Membrane Glycoproteins/analysis , Tumor Cells, Cultured/drug effects , Vinblastine/pharmacology
2.
Cancer Res ; 50(12): 3670-4, 1990 Jun 15.
Article in English | MEDLINE | ID: mdl-2340516

ABSTRACT

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.


Subject(s)
Carcinoma, Renal Cell/drug therapy , Dihydropyridines/pharmacology , Diltiazem/pharmacology , Kidney Neoplasms/drug therapy , Papaverine/pharmacology , Vinblastine/pharmacology , Calcium/antagonists & inhibitors , Chemical Phenomena , Chemistry , Drug Resistance , Humans , Tumor Cells, Cultured/drug effects
3.
J Urol (Paris) ; 96(3): 121-7, 1990.
Article in French | MEDLINE | ID: mdl-1976711

ABSTRACT

In experimental cell lines and in some human tumors, calcium antagonists reversed multidrug resistance in vitro. So far, clinical trials have not been very rewarding as intrinsic cardiovascular activities of these compounds impeded a sufficient dosage. Renal cell carcinomas are considered to be good models for the evaluation of this new therapeutic concept. In 35 primary human renal cell carcinomas, the potency of 7 different calcium antagonists in combination with vinblastine monotherapy was examined in a tetrazolium-based microculture assay (MTT test) in order to circumvent chemoresistance. Substances derived from piperazine (flunarizine) showed only minor effects in this respect. The calcium antagonists of the papaverine type such as Verapamil etc. revealed the strongest reversal of chemo-resistance. Derivatives of benzothiazepine (diltiazem) or of dihydropyridine (nifedipine etc.) acted similarly and reached about 70% of the Verapamil activity. All calcium antagonists tested lead to significant enhancement of vinblastine cytotoxicity. In particular, the new stereoisomer R-Verapamil, which showed strong reversal of resistance but which exerts 10 times lower cardiovascular side effects than racemic Verapamil, seems to be suitable for further evaluation with regard to the clinical application.


Subject(s)
Calcium Channel Blockers/pharmacology , Carcinoma/drug therapy , Kidney Neoplasms/drug therapy , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Drug Resistance , Drug Therapy, Combination , Humans , In Vitro Techniques , Membrane Glycoproteins/metabolism , Vinblastine/pharmacology
SELECTION OF CITATIONS
SEARCH DETAIL
...