title: In vivo characterization of combination antitumor chemotherapy with calcium channel blockers and cis-diamminedichloroplatinum(II).
abstract: We have examined nifedipine, a dihydropyridine class calcium channel blocker, for ability to overcome cis-diamminedichloroplatinum(II) (cisplatin) resistance in a murine tumor line variant, B16a-Pt, which we developed for resistance to cisplatin. Nifedipine significantly enhanced the antitumor actions of cisplatin against primary subcutaneous B16a-Pt tumors and their spontaneous pulmonary metastases. We have characterized, in vivo, the pharmacokinetics and dose-response interactions between nifedipine and cisplatin. We now report our studies designed to compare, in vivo, the efficacy of nifedipine and other calcium active compounds including: (a) structurally similar calcium channel blockers (nimodipine, nicardipine) from the dihydropyridine class, (b) structurally different calcium channel blockers from the benzothiazepine (diltiazem) and the phenylalkylamine (verapamil) classes, and (c) calmodulin antagonists (trifluoperazine and calmidazolium) for ability to enhance the antitumor action of cisplatin. Nifedipine was included as the standard or reference compound. In these studies verapamil and diltiazem failed to enhance the antitumor actions of cisplatin as did both calmodulin antagonists. Our findings suggest that nifedipine has a greater degree of specificity for B16a-Pt cells than structurally different calcium channel blockers from other chemical classes (i.e., diltiazem and verapamil), or the two calmodulin antagonists (i.e., trifluoperazine and calmidazolium). We concluded that nifedipine interacts with specific target site(s) which are not accessible by verapamil, by diltiazem, or by the calmodulin antagonists. Surprisingly, the two dihydropyridine class calcium channel blockers, nimodipine and nicardipine, also failed to enhance cisplatin's antitumor actions despite the fact that their specificity and kinetics for binding to the dihydropyridine receptor component of the calcium channel favors them (nimodipine and nicardipine) over nifedipine. Therefore, we postulate that the synergism between cisplatin and nifedipine is independent of the latter's effect on the voltage sensitive, slow inward calcium channel. We suggest that cisplatin cytotoxicity is enhanced by nifedipine's interaction with an as yet unidentified specific "target site," as opposed to nonspecific interactions with the tumor cell plasma membrane or specific interactions with calmodulin or the P-glycoprotein (which is responsible for pleiotropic resistance).
authors.affiliation: Department of Radiation Oncology, Wayne State University, Detroit, Michigan 48202.
authors.forename: J M
authors.initials: JM
authors.lastname: Onoda
authors.forename: K K
authors.initials: KK
authors.lastname: Nelson
authors.forename: J D
authors.initials: JD
authors.lastname: Taylor
authors.forename: K V
authors.initials: KV
authors.lastname: Honn
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002945:Cisplatin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004110:Diltiazem / Q000493:pharmacokinetics / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007093:Imidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D009529:Nicardipine / Q000493:pharmacokinetics / Q000627:therapeutic use; D009543:Nifedipine / Q000493:pharmacokinetics / Q000627:therapeutic use; D014268:Trifluoperazine / Q000493:pharmacokinetics / Q000627:therapeutic use; D014700:Verapamil / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D002121:Calcium Channel Blockers; D007093:Imidazoles; D014268:Trifluoperazine; C031938:calmidazolium; D014700:Verapamil; D009529:Nicardipine; D004110:Diltiazem; D009543:Nifedipine; D002945:Cisplatin