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).
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.
Alexanian
A R
AR
Biochemical Pharmacology in the Institute of Biochemisty, Armenian Academy of Sciences, Yerevan. aalexanian@vines.colostate.edu
Arutyunian
N S
NS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000276:immunology / Q000302:isolation & purification; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002462:Cell Membrane / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D006801:Humans; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D014750:Vincristine / Q000494:pharmacology
C404413:AR-2 compound; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002147:Calmodulin; D010880:Piperidines; D014750:Vincristine; D004317:Doxorubicin