title: In vitro and in vivo assessment of activity of new anilino-substituted analogues of amsacrine against Lewis lung carcinoma.
abstract: A number of new anilino ring variants of the anti-tumour drug amsacrine have been synthesised and their anti-tumour activity evaluated. In vitro selectivity, as measured by the logarithmic ratio of IC50 growth inhibition assays against P388 leukaemia and Lewis lung carcinoma cells, was significantly correlated with the increase in life span in vivo with the P388 leukaemia and Lewis lung lines, whereas the growth inhibition IC50 values alone correlated with the dose potency in mice. It was thus possible to predict both in vivo anti-tumour activity and dose potency, identifying compounds with high therapeutic activity, using a combination of two in vitro assays. Two new compounds have been identified which provide, along with an acridine-substituted analogue of amsacrine which is at present in clinical trial (CI-921), a high proportion of cures against the Lewis lung tumour in vivo. Since amsacrine is thought to interact with the enzyme topoisomerase II, and because the anilino group of 9-anilinoacridine derivatives is thought to project from the DNA intercalation site of the drug-DNA complex, these compounds may be of particular interest in mode of action studies.
authors.affiliation: Cancer Research Laboratory, University of Auckland Medical School, New Zealand.
authors.forename: G W
authors.initials: GW
authors.lastname: Rewcastle
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
authors.forename: W R
authors.initials: WR
authors.lastname: Wilson
authors.forename: B C
authors.initials: BC
authors.lastname: Baguley
mesh_terms: D000677:Amsacrine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004247:DNA / Q000378:metabolism; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000677:Amsacrine; D004247:DNA