In vitro assessment of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide, a DNA-intercalating antitumour drug with reduced sensitivity to multidrug resistance.
The successful treatment of cancer requires the identification of new drugs with novel actions. N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride (DACA) is a topoisomerase II-targeted antitumour drug with curative activity against murine Lewis lung carcinoma. DACA was assessed for novel patterns of growth inhibition using normal and multidrug-resistant human cell lines. Cells were cultured in 96-well microtitre trays and tested against DACA and related topoisomerase-directed drugs, including amsacrine, etoposide and doxorubicin, and drug concentrations for 50% growth inhibition (IC50 or GI50 values) were determined. In a series of Jurkat leukaemia lines characterised as exhibiting atypical multidrug resistance, DACA was to a large extent capable of overcoming multidrug resistance exhibited towards the other topoisomerase-directed agents. DACA was also tested against the National Cancer Institute 60-tumour-specific cell-line panel (GI50 values ranging from 420 to 5,400 nM; mean, 2,100 nM) and against a series of primary cultures of surgically excised melanomas (IC50 values ranging from 60 to 1,600 nM; mean, 590 nM). DELTA values (deviations of logarithmic IC50 or GI50 values from the mean) were calculated and compared by correlation analysis. The standard deviation of DELTA values was found to be lower for DACA than for the other topoisomerase II-directed drugs amsacrine, etoposide, doxorubicin and mitozantrone in both the cell lines and the primary cultures. These lower standard deviations appear to have resulted from the reduced susceptibility of DACA to both P-glycoprotein- and topoisomerase II-mediated multidrug-resistance mechanisms occurring naturally in cell lines and primary cultures.
Finlay
G J
GJ
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Marshall
E
E
Matthews
J H
JH
Paull
K D
KD
Baguley
B C
BC
D000166:Acridines; D000609:Aminoacridines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000187:drug effects; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D007938:Leukemia / Q000188:drug therapy*; D008545:Melanoma / Q000188:drug therapy*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000166:Acridines; D000609:Aminoacridines; D000970:Antineoplastic Agents; D007364:Intercalating Agents; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide; D004264:DNA Topoisomerases, Type I