title: High uptake of RSU 1069 and its analogues melanotic melanomas.
abstract: RSU 1069 and RSU 1164 are electron affinic agents that contain a nitro group together with a weakly basic alkylating aziridine moiety, and they represent lead compounds in the development of dual-function, bioreductive, hypoxic cell radiosensitizers. We studied the pharmacokinetics of these drugs in mice carrying KHT sarcoma. Lewis lung carcinoma, and B16 melanoma. Following an i.p. dose of 80 mg/kg, absorption was rapid and the elimination t1/2 was in the region of 30 min for both agents. Maximal tumour levels were 91, 16 and 19 microgram/ml for RSU 1069 and 109, 26 and 28 microgram/ml for RSU 1164 in. the B16, KHT and Lewis lung tumours, respectively. In B16 melanoma these levels corresponded to tumour:plasma ratios of 3.8 for RSU 1069 and 3.7 for RSU 1164. Cellular uptake of RSU 1069, RSU 1164 and a related compound, RB 7040, was measured in vitro as a function of extracellular pH. Melanotic cells from both B16 melanoma and HX118, a human tumour xenograft, showed substantially greater accumulation of these weakly basic sensitizers than any other cell type examined. Ratios of intra-:extracellular concentration (Ci/Ce) for RSU 1069 were around unity and independent of pH for Lewis lung cells and HX34 amelanotic melanoma cells, whereas ratios of up to 3 and 5 were obtained in B16 and HX118 cells, respectively. The highest measured value of Ci/Ce was 15 for RSU 1164 in HX118 cells at pH 8.4; this compares with a ratio of 1.5 for HX34 cells at the same pH. These studies indicate that the high levels of uptake of the weakly basic sensitizers into melanotic melanoma in vivo is a cell-mediated phenomenon and may be due to a lower average intracellular pH in the melanotic cells.
authors.affiliation: MRC Radiobiology Unit, Chilton, Didcot, Oxon UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Walling
authors.forename: J
authors.initials: J
authors.lastname: Deacon
authors.forename: S
authors.initials: S
authors.lastname: Holliday
authors.forename: I J
authors.initials: IJ
authors.lastname: Stratford
mesh_terms: D000818:Animals; D002460:Cell Line; D002463:Cell Membrane Permeability; D003851:Deoxyribonucleases; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D003012:Microbial Collagenase; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D012513:Sarcoma, Experimental / Q000378:metabolism; D014018:Tissue Distribution; D014357:Trypsin; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: C049944:1-(2-nitro-1-imidazoly)-3-(2,3-dimethylaziridino)-2-propanol; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole; D003851:Deoxyribonucleases; D014357:Trypsin; D003012:Microbial Collagenase