Resistance of CHO cells expressing P-glycoprotein to cyclopropylpyrroloindole (CPI) alkylating agents.
Several new antitumor agents belonging to the class of minor groove binders that are able to form covalent bonds with DNA via a cyclopropylpyrroloindole (CPI) group are susceptible to a multidrug resistance (MDR) phenotype in Chinese hamster ovary (CHO) cells. The multidrug resistant CCHR-C5 cell line was 16-, 23- and 13-fold more resistant to the analogs U-73,975, U-77,779 and U-80,244, respectively, although its cytotoxic response to the parent compound CC-1065 was similar to the response of the drug-sensitive wild-type cells (AuxB1). For a sequence of MDR cell lines showing increasing expression of P-glycoprotein (Pgp) there were corresponding increments in the level of resistance to U-73,975, arguing that Pgp is the key determinant in resistance of the MDR cells to CPI agents. MDR cells treated with U-73,975 showed diminished generation of covalent adducts on DNA as well as increased resistance to cytotoxicity.
Zsido
T J
TJ
Department of Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY 14263.
Beerman
T A
TA
Meegan
R L
RL
Woynarowski
J M
JM
Baker
R M
RM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001572:Benzofurans; D016466:CHO Cells; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D053138:Cyclohexenes; D004249:DNA Damage; D004351:Drug Resistance; D000080890:Duocarmycins; D007211:Indoles / Q000494:pharmacology*; D007933:Leucomycins / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000477:Alkylating Agents; D000970:Antineoplastic Agents; D001572:Benzofurans; D003509:Cyclohexanecarboxylic Acids; D053138:Cyclohexenes; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D008562:Membrane Glycoproteins; C018782:CC 1065; C060090:adozelesin; D014508:Urea; C072257:bizelesin