QUANTITATIVE MODELS FOR GROWTH-INHIBITION OF HUMAN-LEUKEMIA CELLS BY ANTI-TUMOR ANTHRACYCLINE DERIVATIVES

  • 1 January 1979
    • journal article
    • research article
    • Vol. 39  (9) , 3661-3672
Abstract
A batch elution method with hydroxylapatite was developed to assay DNA damage by 10 antitumor anthracycline derivatives [adriamycin, 4-epiadriumyein, carminomyein, 4-demethoxydaunorabiein, daunorubicin, adriamycin-14-benzoate, adriamycin-14-(1-naphthaloneacetate), adriamycin-14-octanoate, N-acetyldaunorubicin and N-trifluoroacetyl-adriamycin-14-ralerate] and was standardized with respect to the kinetics of unwinding, size of the alkaline unwinding unit, and fidelity of selective elution of single and double-stranded DNA. The method was applied to a study of 10 antitumor anthracycline derivatives which inhibit growth of CCRF-CEM human leukemia cells over a range of potencies exceeding 4 orders of magnitude. The derivatives, including Adriamycin, daunorubicin and carminomycin, vary in structure at C-4 and C-13, with substitutions at C-14 and N and streochemical differences at C-4''. In a static model (fixed drug concentrations and incubation times), the potency [1/ID37 (concentration of agent that inhibits cell growth by 37%)] of 9 of the 10 derivatives may be expressed as functions of DNA damage (n), inhibition of thymidine incorporation (l) and drug retention (r): kb ID37 = Ka(r/l .cntdot. n) with a coefficient of correlation of > 0.99. A kinetic model with 4-demethoxydaunorubicin (varying concentrations and incubation times) was also described. Following initial uptake and a period of rapid loss after cells are washed free of excess drug, the change in agent concentration in the cells follows first-order kinetics. The cell index (cell number after 50 h in drug-free growth medium/cell number after initial 2 h exposure with drug) may be expressed linerly in terms of the kinetics of drug loss (coefficient of correlation, > 0.98), or as functions of 1/n (coefficient of correlation, > 0.958), 1/l .cntdot. n (coefficient of correlation, > 0.963), or r/l .cntdot. n (coefficient of correlation, > 0.963). These studies may be used to define a class of similarly acting anthracycline agents and to give some insight into the mechanism of action of the agents that fall within the class.