Cyclophosphamide metabolite inducing apoptosis in RLS mouse lymphosarcoma cells is a substrate for P-glycoprotein.
RLS lymphosarcoma characterized by enhanced expression of mdr1a and mdr1b genes encoding P-glycoprotein is insensitive to low doses of cyclophosphamide, but is susceptible to its high doses approximating the maximum tolerated doses. Induction of apoptotic death of RLS cells by high doses of cyclophosphamide was demonstrated by cytofluorometry and electrophoresis. Experiments on RLS(40) tumor cells derived from RLS lymphosarcoma and characterized by more intensive expression of mdr1a/1b genes showed that the therapeutic effects of cyclophosphamide increased under conditions of simultaneous suppression of these genes by specific small interfering RNA (siRNA). These findings suggest that active cyclophosphamide metabolite can be a substrate for P-glycoprotein.
Institute of Chemical Biology and Fundamental Medicine, Siberian Division of the Russian Academy of Sciences, Novosibirsk, Russia.
O A
OA
Patutina
N L
NL
Mironova
E B
EB
Logashenko
N A
NA
Popova
V P
VP
Nikolin
G V
GV
Vasil'ev
V I
VI
Kaledin
M A
MA
Zenkova
V V
VV
Vlasov
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000378:metabolism* / Q000494:pharmacology; D004586:Electrophoresis; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D034741:RNA, Small Interfering / Q000235:genetics; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003520:Cyclophosphamide; D034741:RNA, Small Interfering; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3