title: Activity of C-7 substituted cyclic acetal derivatives of mitomycin C and porfiromycin against hypoxic and oxygenated EMT6 carcinoma cells in vitro and in vivo.
abstract: A series of cyclic acetal derivatives of mitomycin C (MC) and porfiromycin (POR) were tested for their ability to kill hypoxic and oxygenated EMT6 tumor cells. Amino methyl acetal and thioacetal substitutions at C-7 of MC and POR dramatically increased the cytotoxicity of the compounds to hypoxic EMT6 tumor cells in vitro but had little effect on the aerobic toxicities. In contrast, a methyl substitution at N1a markedly decreased the aerobic cytotoxicities of the compounds but did not alter the hypoxic cytotoxicities. The POR acetal, BMY-42355, had the largest differential between hypoxic and aerobic cytotoxicities yet observed among MC analogs. Preliminary studies in mice showed that BMY-42355 had good antineoplastic activity when used alone or in combination with radiation and was less toxic than POR; the therapeutic ratio of this compound in these initial studies was higher than those of either MC or POR.
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: S
authors.initials: S
authors.lastname: Rockwell
authors.forename: S R
authors.initials: SR
authors.lastname: Keyes
authors.forename: R
authors.initials: R
authors.lastname: Loomis
authors.forename: M
authors.initials: M
authors.lastname: Kelley
authors.forename: D M
authors.initials: DM
authors.lastname: Vyas
authors.forename: H
authors.initials: H
authors.lastname: Wong
authors.forename: T W
authors.initials: TW
authors.lastname: Doyle
authors.forename: A C
authors.initials: AC
authors.lastname: Sartorelli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D015687:Cell Hypoxia; D002470:Cell Survival; D003131:Combined Modality Therapy; D004354:Drug Screening Assays, Antitumor; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008937:Mitomycins / Q000627:therapeutic use*; D011160:Porfiromycin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D008937:Mitomycins; D011160:Porfiromycin