Reversal of drug resistance in sarcoma-45 by the new calmodulin antagonist--trihydrochloride of [1,2,5-trimethyl-4-phenyl-4-beta-[N-(beta-ethylamino)-N-4'-methoxybe nzy l]-ethylamino] piperidine (AR-2). Invest New Drugs 1999;17(2):105-10
Date
01/19/2000Pubmed ID
10638481DOI
10.1023/a:1006397014409Scopus ID
2-s2.0-0032805142 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
The anti-drug resistance effect of three derivatives (AR-1, AR-2 and AR-3) of [1,2,5-trimethyl-4-phenyl-4-beta-(N,N-disubstituted-ethylamino)] piperidines, that were evaluated as calcium and calmodulin antagonists, was studied on doxorubicin (ADM) and vincristine (VCR) resistant Sarcoma-45 inoculated rats. Treatment with ADM (5 mg/kg) or VCR (3 mg/kg) alone, as well as with AR-1, AR-2 or AR-3 (50 mg/kg) alone, had no effect on tumor growth. However, AR-2 in dose 50 mg/kg (calmodulin antagonist), but not AR-1 and AR-3 (calcium channel blocker), administered with ADM (5 mg/kg) or VCR (3 mg/kg), significantly suppressed tumor growth 80% and 70%, respectively. Two rats treated with ADM/AR-2 and one treated with VCR/AR-2 were cured. 170 kDa protein was purified from sarcoma-45 tumor cells to apparent homogeneity by successive steps of phosphocellulose, DEAE-cellulose, and AR-2-coupled sepharose chromatography. The protein proved to be immunopositive with the P-glycoprotein-specific monoclonal antibody. It is concluded that the effect of AR-2 can be explained by both hydrophobic and electrostatic interaction with a protein target (170 kDa P-glycoprotein) in resistant sarcoma-45 tumor cell's membrane.
Author List
Alexanian AR, Arutyunian NSAuthor
Arshak R. Alexanian VMD, PhD Adjunct Associate Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntibodies, Monoclonal
Antineoplastic Agents
Calmodulin
Cell Membrane
Doxorubicin
Drug Interactions
Drug Resistance, Neoplasm
Humans
Piperidines
Rats
Rats, Sprague-Dawley
Sarcoma, Experimental
Vincristine
