[Role of calcium antagonists in the treatment of chemoresistant cancer of the kidney].
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.
Mickisch
G
G
Service d'Urologie, CHU Mannheim, Université de Heidelberg, RFA.
Kössig
J
J
Tschada
R
R
Keilhauer
G
G
Schlick
E
E
Alken
P
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy*; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D006801:Humans; D066298:In Vitro Techniques; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008562:Membrane Glycoproteins / Q000378:metabolism; D014747:Vinblastine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D008562:Membrane Glycoproteins; D014747:Vinblastine