An in vitro colony formation assay was used to determine the efficacy of in vitro
therapy with
1,3-bis(2-chloroethyl)-1-nitrosourea (
BCNU) on a rat
brain tumor. The fraction of clonogenic cells surviving in vivo
therapy was determined by a comparison between the in vitro colony-forming capacity of cells derived from previously treated and untreated
tumors. With this intracerebral solid
tumor a direct correlation was found between the surviving fraction of cells and animal survival, implying that the in vitro assay system is a reliable test of
therapeutic effect. The
BCNU dose-response curve was exponential up to a dose of 0.75 times the LD10 dose with little additional cell kill noted at higher
drug levels. This plateau does not appear to represent a resistant subpopulation of cells, since
retreatment of
tumors derived from cells surviving an LD10 dose were as sensitive to
BCNU as those with no prior
drug exposure. Instead, it may represent, at least in part, failure of the
drug to reach and/or enter cells in all parts of solid
tumors. On the average
BCNU doses of 0.75 times the LD10 dose or greater resulted in slightly more than a 3-log cell kill and doubled the life-span for our
tumor-bearing animals. The finding that an increase in animal life-span requires at least a 1-log
tumor cell kill indicates that survival studies with intracranial
tumor models may be insensitive to single courses of many chemotherapeutic agents with modest but significant antitumor activity.