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.
Department of Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY 14263.
T J
TJ
Zsido
T A
TA
Beerman
R L
RL
Meegan
J M
JM
Woynarowski
R M
RM
Baker
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