Experimental antitumor activity of new azathioprine analogues

Two newly synthesized azathioprine (AZA) analogues, 6-(1,2-dimethyl-4-nitro-5-imidazolyl)thiopurine (Met-AZA) and 6-(2-methyl-5-nitro-4-imidazolyl)thiopurine (IZO-AZA), were investigated against KB human tumor cells. In 5 transplantable murine tumor models, including sc Sa180, sc Ca755, ip LL and ip leukemias; L1210 and P388 both drugs were found to be antitumor active in all the experiments carried out regardless of dosing regimen or the route of administration. Similar good activity was shown in the KB, ip Sa180, and Ca755 systems and partly against LL as compared to AZA. However, Met-AZA against ip P388 demonstrated therapeutic advantage following qd 1-9 daily dosing, 0.33 log10 tumor cell kill; therapeutic index (TI = ILSmax/ILS 25) = 2, and ILS = 69% in comparison to AZA and IZO-AZA, TI = 1.3, 1.2, and ILS = 31%, 40%, respectively. Met-AZA is comparable to AZA, while seeming to display greater antileukemic activity than AZA.