title: Comparative in vitro evaluation of dithiane analogs of tiapamil, Ro 11-2933, Ro 44-5911 and Ro 44-5912 as multidrug resistance modulators.
abstract: The analogs of tiapamil are highly active modifiers of P-glycoprotein-mediated multidrug resistance (MDR) in vitro. The activity of three analogs of tiapamil, Ro 11-2933, Ro 44-5911 and Ro 44-5912, was compared in K562/DXR and MCF-7/DXR cell lines, using flow cytometry for the determination of intracellular daunorubicin accumulation and MTT assays for the cytotoxic evaluation of the modulators combined or not with daunorubicin. Ro 44-5911 and Ro 44-5912 were not intrinsically more toxic than DL-verapamil and exhibited a significantly higher reversing effect. Ro 44-5912 was shown slightly more efficient than Ro 44-5911 for reversing daunorubicin cytotoxicity. Ro 11-2933 was found to be the most potent in modulating MDR but was not significantly more active than Ro 44-5912. These two compounds were able to achieve a near complete reversion (above 80%) at 5 mumol/I. However, the cytotoxicity of Ro 11-2933 was higher with an IC50 near 20 mumol/I in both K562 and MCF7 cell lines. Our results indicate that tiapamil derivatives are promising compounds for MDR modulation. Among them Ro 11-2933 and Ro 44-5912 seem to be particularly interesting for in vivo evaluations.
authors.affiliation: Centre Alexis Vautrin, Laboratoire de Recherche en Oncologie, Vandoeuvre les Nancy, France.
authors.forename: M
authors.initials: M
authors.lastname: Abderrabi
authors.forename: S
authors.initials: S
authors.lastname: Marchal
authors.forename: J L
authors.initials: JL
authors.lastname: Merlin
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003630:Daunorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000378:metabolism; D011437:Propylamines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D011437:Propylamines; C102820:Ro 44-5911; C095183:Ro 44-5912; C054970:Ro 11-2933; D014700:Verapamil; D003630:Daunorubicin