Comparison of in vivo and in vitro drug sensitivities of Lewis lung carcinoma and P388 leukaemia to analogues of amsacrine.

The activity of several clinical agents (5-fluorouracil, methotrexate, adriamycin, daunorubicin, mitoxantrone and amsacrine) and of a number of analogues of amsacrine, including the 4-methyl,5-(N-methyl)carboxamide derivative (CI-921) which is at present in clinical trial, has been compared in vivo against Lewis lung carcinoma (LL) and P388 leukaemia in mice, and against corresponding cell lines in cell culture. All derivatives were active against i.p. inoculated P388 leukaemia whereas only some were active against i.v. inoculated LL cells. The relative in vitro activities in the two cell lines, as measured by growth inhibition (IC50) assays, varied from equitoxic to 26-fold more active with P388 cells than with LL cells. The in vivo activity of these drugs against i.v. inoculated LL relative to i.p. inoculated P388 could be predicted with a high degree of significance from the ratio of in vitro activities in the 2 cell lines. However, this correlation did not appear to reflect cell line selectivity alone, since, when P388 cells were inoculated i.v. rather than i.p., drug sensitivity closely matched that of the LL tumour. This observation suggests a dominant role for pharmacological variables in determining the in vivo activity of amsacrine analogues, and underlines the importance of standardising tumour site in the determination of antitumour spectrum. Nevertheless, the correlation of selective in vitro toxicity for cultured LL cells with high activity against remotely implanted tumours demonstrates the utility of in vitro tests in identifying amsacrine analogues with improved clinical potential.