11-acetyl-8-carbamoyloxymethyl-4-formyl-6-methoxy-14-oxa-1-11-diazatetracyclo(7.4.1.0.0)tetradeca-2-4-6-trien-9-yl-acetate and Carcinoma--Small-Cell

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.

Topics: Affinity Labels; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Azides; Biotransformation; Carcinoma, Small Cell; Cell Survival; Dihydropyridines; Drug Resistance, Multiple; Humans; KB Cells; Lung Neoplasms; Male; Mice; Mice, Nude; Nasopharyngeal Neoplasms; Oxazines; Transplantation, Heterologous; Tritium; Vinblastine

The antitumor effects of FK317, a novel substituted dihydrobenzoxazine, were evaluated using human tumor xenografts (small cell lung cancer, non-small cell lung cancer, stomach cancer, colon cancer, pancreatic cancer, breast cancer, cervical cancer and ovarian cancer). Tumor growth-inhibitory effects and the effective dose-range of FK317 were much stronger and broader, respectively, than those of reference drugs such as mitomycin C, adriamycin, cisplatin, taxol and irinotecan. Furthermore, the body weight decrease and myelosuppression in FK317-treated mice were less than in the animals given any of the reference drugs. To explain this tumor selectivity, the distribution of FK317 was investigated after dosing tumor-bearing mice with the 14C-labelled compound. The concentration of FK317 in tumor tissues was relatively low, and long tumor retention was not observed. However, thin-layer chromatographic separation revealed that the radioactivity in the tumor resided mainly in strongly cytotoxic metabolites, while that in other tissues resided mainly in non-cytotoxic metabolites. These results suggest that FK317 shows strong antitumor activity without side effects, and one reason for this is its specific metabolite pattern. FK317 is now undergoing phase I clinical trials.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Biotransformation; Body Weight; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cisplatin; Colonic Neoplasms; Doxorubicin; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; HeLa Cells; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mitomycin; Neoplasm Transplantation; Neoplasms, Experimental; Ovarian Neoplasms; Oxazines; Stomach Neoplasms; Tissue Distribution; Transplantation, Heterologous; Tumor Cells, Cultured; Tumor Stem Cell Assay