Different effects of FK317 on multidrug-resistant tumor in vivo and in vitro.
FK317, a novel substituted dihydrobenzoxazine, was examined for antitumor effects on multidrug-resistant (MDR) tumor cells in vitro and in vivo. In nude mice, FK317 markedly inhibited the growth of s.c. implanted KB-V1 vinblastine (VLB)-resistant human epidermal carcinoma KB cells, as well as the parent cells (KB-3-1). However, KB-V1 showed much greater resistance to FK317 than to VLB and adriamycin (ADM) in the in vitro study. This resistance was reversed by the addition of verapamil, whereby intracellular accumulation of FK317 in the KB-V1 cells was also decreased. After incubation of FK317 in human and mouse blood, it was shown to be rapidly metabolized to a monodeacetylated form, and slowly metabolized further to a dideacetylated form. With the removal of the acetyl groups from FK317, resistance indexes in KB-V1 and SBC-3/ADM, ADM-resistant human lung carcinoma, decreased. In addition, photolabeling of P-glycoprotein with [3H]azidopine in KB-V1 plasma membrane was completely inhibited by FK317, but not by the deacetylated metabolites. These results indicate that FK317 is metabolized to deacetylated forms, which do not bind to P-glycoprotein and are incorporated into MDR cells, causing cytotoxic effects.
Naoe
Y
Y
Department of Pharmacology, Fujisawa Pharmaceutical Co., Osaka.
Inami
M
M
Takagaki
S
S
Matsumoto
S
S
Kawamura
I
I
Nishigaki
F
F
Tsujimoto
S
S
Manda
T
T
Shimomura
K
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000345:Affinity Labels; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D001386:Azides / Q000493:pharmacokinetics; D001711:Biotransformation; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004095:Dihydropyridines / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D006801:Humans; D007624:KB Cells; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000473:pathology; D010078:Oxazines / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D014183:Transplantation, Heterologous; D014316:Tritium; D014747:Vinblastine / Q000633:toxicity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000970:Antineoplastic Agents; D001386:Azides; D004095:Dihydropyridines; D010078:Oxazines; D014316:Tritium; D014747:Vinblastine; C041130:azidopine; C112463:FK 317 dihydrobenzoxazine