title: In vivo antitumor activity of sparsomycin and its analogues in eight murine tumor models.
abstract: Sparsomycin (Sm) is a known inhibitor of ribosomal protein synthesis with an attractive anticancer potential. Recently, several analogues of Sm which are more active than the parent drug were selected for further study on the basis of in vitro investigations. Six analogues as well as the parent drug were tested for their antitumor activity in eight in vivo murine tumor models: P388 and L1210 leukemias, RC renal cell carcinoma, B16 melanoma, C38 colon carcinoma, LL Lewis lung carcinoma, C22LR osteosarcoma and M5076 sarcoma. Sm itself appeared to have only borderline activity on L1210 leukemia. The analogues that were most active in vitro showed also the highest in vivo activity. The most sensitive tumors were RC, L1210 and P388. Minimal activity was found on B16 and no activity on C22LR, M5076, C38 and LL. The most active compounds are deshydroxy-Sm, ethyl-deshydroxy-Sm and n-pentyl-Sm. There was a considerable loss of activity when L1210 leukemia was implanted sc while the drugs were administered iv. Only one drug, ethyl-deshydroxy-Sm appeared to be active in this assay. No single most effective compound could be found in this study. The overall activity of Sm and its analogues is moderate. The three analogues which show high activity in three ascitic tumors will be further investigated using human tumor xenograft models.
authors.affiliation: Dept. of Internal Medicine, St. Radboud University Hospital, Nijmegen, The Netherlands.
authors.forename: Z
authors.initials: Z
authors.lastname: Zylicz
authors.forename: D J
authors.initials: DJ
authors.lastname: Wagener
authors.forename: H
authors.initials: H
authors.lastname: van Rennes
authors.forename: E
authors.initials: E
authors.lastname: van der Kleijn
authors.forename: P
authors.initials: P
authors.lastname: Lelieveld
authors.forename: L A
authors.initials: LA
authors.lastname: van den Broek
authors.forename: H C
authors.initials: HC
authors.lastname: Ottenheijm
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D003110:Colonic Neoplasms / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D007928:Lethal Dose 50; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D012516:Osteosarcoma / Q000188:drug therapy; D012513:Sarcoma, Experimental / Q000188:drug therapy; D013033:Sparsomycin / Q000031:analogs & derivatives / Q000627:therapeutic use* / Q000633:toxicity
chemical_list: D000903:Antibiotics, Antineoplastic; D013033:Sparsomycin