title: In vivo properties of the conjugates of mitomycin C with estradiol benzoate and estradiol: pharmacokinetics and antitumor characteristics against P388 leukemia and sarcoma 180.
abstract: Conjugates of mitomycin C (MMC) with estradiol benzoate and estradiol via glutaric acid, abbreviated to EB-glu-MMC and E-glu-MMC, respectively, as previously reported, were examined concerning their pharmacokinetic behaviors and antitumor effects against two kinds of general and popular tumors, P388 leukemia and Sarcoma 180. EB-glu-MMC and E-glu-MMC were dissolved in propylene glycol. Their solution was administered intraperitoneally to rats and mice in order to examine their plasma concentration-time profiles and antitumor characteristics, respectively. After the administration of EB-glu-MMC, EB-glu-MMC was detected slightly in blood only in the initial stage, while E-glu-MMC and MMC were observed there for a prolonged period. In the administration of E-glu-MMC, a similar phenomenon was observed but the drug retention effect seemed lower than that in EB-glu-MMC. In the antitumor test against P388 leukemia, E-glu-MMC exhibited a better effect than EB-glu-MMC; however, neither conjugate surpassed the effect of MMC. The toxic side effect was improved in each conjugate. As to the growth inhibition against Sarcoma 180, EB-glu-MMC and E-glu-MMC produced good effect and improved the toxic side effect. Especially, in the administration of EB-glu-MMC at the dose of 30 mg eq MMC/kg, a decrease in tumor volume was observed in the latter stage. EB-glu-MMC and E-glu-MMC were demonstrated to produce prolonged retention, to enter the systemic circulation to a fair extent, and to exhibit a good effect against the general solid tumor, Sarcoma 180, in vivo.
authors.affiliation: Department of Clinical Pharmacy, Hoshi University, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Ishiki
authors.forename: H
authors.initials: H
authors.lastname: Onishi
authors.forename: Y
authors.initials: Y
authors.lastname: Machida
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D007274:Injections, Intraperitoneal; D007941:Leukemia P388; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016685:Mitomycin / Q000493:pharmacokinetics / Q000627:therapeutic use; D008937:Mitomycins; D051381:Rats; D017208:Rats, Wistar; D012510:Sarcoma 180
chemical_list: C108997:1a-(4-(3-benzoyloxy-1,3,5(10)-estratrien-17-yloxycarbonyl)butyryl)mitomycin C; C108998:1a-(4-(3-hydroxy-1,3,5(10)-estratrien-17-yloxycarbonyl)butyryl)mitomycin C; D000970:Antineoplastic Agents; D008937:Mitomycins; D004958:Estradiol; D016685:Mitomycin