Multidrug resistance is a component of V79 cell resistance to the alkylating agent adozelesin.
Adozelesin is a highly potent alkylating agent which has entered clinical trials based on its unique mechanisms of action and broad-spectrum antitumor activity in vivo. V79 cells resistant to adozelesin (V79/AdoR) were not resistant to the alkylating agent cisplatin but showed the phenotypic and genotypic characteristics of multidrug resistance. Thus V79/AdoR was cross-resistant to several structurally and functionally unrelated drugs, resistance was reversed by verapamil, and the resistant cell line expressed mdr mRNA and p170 glycoprotein. Also, adozelesin uptake and the amount of drug alkylated to DNA was much lower in the resistant cell line as compared to the sensitive parent. However, even with the same amount of drug bound to DNA (10 fmol/micrograms DNA) the survival of V79/S approximately 15% survival) was much lower than that of V79/AdoR (approximately 80%). Therefore the resistance of V79/AdoR cannot be explained solely by the multidrug resistance mechanism (i.e., lower drug uptake and less drug alkylation to DNA), which suggests that multiple mechanisms may account for resistance to adozelesin. V79/AdoR showed different levels of cross-resistance to several adozelesin analogues. The analogues could be divided into 2 groups; those with very low partition coefficients (log P < 2 as compared to 2.74 for adozelesin) had low levels of cross-resistance, whereas analogues with higher partition coefficients (log P > 2.4) were cross-resistant to adozelesin.
Bhuyan
B K
BK
Department of Cancer and Infectious Diseases Research, Upjohn Company, Kalamazoo, Michigan 49001-0199.
Smith
K S
KS
Kelly
R C
RC
Adams
E G
EG
Abraham
I
I
Sampson
K E
KE
D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001572:Benzofurans; D019328:Buthionine Sulfoximine; D002460:Cell Line; D006224:Cricetinae; D003509:Cyclohexanecarboxylic Acids / Q000378:metabolism / Q000494:pharmacology*; D053138:Cyclohexenes; D004247:DNA / Q000378:metabolism; D004351:Drug Resistance; D000080890:Duocarmycins; D007211:Indoles; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D001572:Benzofurans; D003509:Cyclohexanecarboxylic Acids; D053138:Cyclohexenes; D000080890:Duocarmycins; D007211:Indoles; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; C060090:adozelesin; D004247:DNA; D014700:Verapamil