title: Circumvention of inherent or acquired cytotoxic drug resistance in vitro using combinations of modulating agents.
abstract: OBJECTIVE
  Modulating agents are used to circumvent drug resistance in the clinical setting. However achievable serum concentrations are often lower than those which are optimal in vitro. Combination of modulating agents with non-overlapping toxicities may overcome this obstacle. We have investigated combinations of three modulating agents (quinine, verapamil, and cinnarizine) to circumvent inherent or acquired resistance to the cytotoxic drugs doxorubicin, vincristine and paclitaxel.
  
  
  METHODS
  Dose-response curves to cytotoxic drugs in the presence/absence of modulating agents were determined using colony formation and cell proliferation assays. Doxorubicin accumulation into cell monolayers was measured by fluorescence spectrophotometry.
  
  
  RESULTS
  Greater (1.9-fold) sensitisation to particular cytotoxic drugs was observed for certain combinations of modulating agents compared to individual effects. The most effective combination was quinine-plus-verapamil with the cytotoxic drug doxorubicin. This increase in sensitivity was associated with increased doxorubicin accumulation. Such enhanced activity was, however, not observed for all combinations of modulating agents or for all studied cytotoxic drugs.
  
  
  CONCLUSIONS
  The findings of the present study suggest certain combinations of modulating agents to have a clinical role in circumventing drug resistance. Particular combinations of modulating agents must be carefully chosen to suit particular cytotoxic drug treatments.
authors.affiliation: School of Sciences, Staffordshire University, Stoke-on-Trent, ST42DF, U.K. david.cadagan@hotmail.com.
authors.forename: David
authors.initials: D
authors.lastname: Cadagan
authors.forename: Stephen
authors.initials: S
authors.lastname: Merry
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002936:Cinnarizine / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D020714:Maximum Tolerated Dose; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002936:Cinnarizine; D014750:Vincristine; D004317:Doxorubicin; D011803:Quinine; D014700:Verapamil; D017239:Paclitaxel
keywords: L929 murine cell line; MCF7 breast cancer cell line; Multidrug resistance; doxorubicin; drug accumulation; modulating agents; paclitaxel; vincristine