Relationship between the structure of analogues of amsacrine and their degree of cross-resistance to adriamycin-resistant P388 leukaemia cells.
A series of derivatives of 9-anilinoacridine related to the anti-leukaemia agent amsacrine have been tested in continuous exposure growth inhibition assays to determine the degree of cross-resistance in the Adriamycin-resistant P/ADR murine leukaemia line. Measured IC50 values for the two cell lines were only poorly correlated (r = 0.51), and cross-resistance as measured by the ratio of IC50 values varied from 2-fold and 272-fold. A high degree of resistance was found to be associated with the presence of amino or substituted amino groups on the acridine ring system. Logarithmic IC50 values were determined for other cell lines (L1210 leukaemia, Lewis lung carcinoma and HCT-8 human colon carcinoma) and were compared with those for the P388 lines to determine the degree of linear correlation. HCT-8 values were strongly correlated with P/ADR values (r = 0.84) while L1210 values correlated strongly with those of the sensitive P388 line (r = 0.98). Values for Lewis lung cells showed an intermediate pattern and correlated with a linear combination of values for both P388 lines (r = 0.88). Examination of available IC50 values for a number of rodent and human cell lines indicates that their sensitivity patterns are either P388-like or else intermediate between P388 and P/ADR. The series of amsacrine derivatives may be useful in characterizing the nature and degree of multidrug-resistance in cultured cell lines.
Baguley
B C
BC
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Finlay
G J
GJ
D000677:Amsacrine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004317:Doxorubicin / Q000627:therapeutic use*; D004351:Drug Resistance; D007941:Leukemia P388 / Q000188:drug therapy*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000677:Amsacrine; D004317:Doxorubicin