Brain-tumor therapy

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Abstract
A recently developed colony formation assay was used to evaluate 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) therapy of a transplantable rat brain tumor model in vivo. A comparison of the in vitro colony forming capacity of treated and untreated tumor cells permits calculation of the fraction of clonogenic tumor cells surviving in vivo therapy. The plateau previously observed on the BCNU dose-response curve is not the result of repair of potentially lethal damage, since no change in the 0.1% of surviving clonogenic tumor cells occurs during the first 2-4 days after treatment. Although reanalysis of the dose-response curve indicates that sublethal damage exists, its repair is probably minimal. The most likely explanation for the observed limitation of the BCNU effect is the drug''s failure to reach all clonogenic cells. A dose of BCNU that kills more than 99.9% of clonogenic tumor cells within 30 min of treatment results in only a 60% decrease in tumor weight by day 14. This disparity is explained by retarded removal of dead cells, and, along with a previously determined 90% cell-kill threshold necessary to appreciate increased animal survival, demonstrates the inherent limitations of measurements of tumor size (including brain scans and clinical patient evaluations) in evaluating the efficacy of brain tumor therapy. Following an LD10 dose of BCNU the surviving clonogenic tumor cells increase in number after a latency period of 2-4 days. During regrowth the cell doubling time is 40 h. Marked variability in tumor response and regrowth was noted. The determination of information regarding disturbed tumor cell kinetics and tumor heterogeneity is essential for the proper planning of combination chemotherapy and multimodality regimens.