A Dose-Response Study of Resistance of Leukemia L1210 to Cyclophosphamide2

Abstract

A series of cyclophosphamide-resistant leukemia sublines were selected by serial drug treatment. Dose-response curves in vivo were determined by following cell outgrowth in drug-treated mice. Dose-response curves of sensitive and resistant lines were similar in form, with a shoulder region indicating accumulation of sublethal damage and an upward concavity of the exponential portion of the curve indicating inhomogeneity of sensitivity in the cell populations. Two-dose fractionation studies were interpreted as evidence that drug-resistant cells could repair sublethal damage, but neither the magnitude of this repair nor the rate of repair differed between sensitive and resistant cells. The dose-response curves differed in slope suggesting either a difference in cell uptake or a difference in intracellular handling of drug as mechanisms of resistance. These studies showed the usefulness of detailed analysis of dose-response curves and suggested the value of correlating dose-response curves with bio-chemical investigations of drug resistance.