The effect of treatment with single and split doses of spirohydantoin mustard on the growth delay of 9L rat brain tumor multicellular spheroids.

The effects of single and split doses of spirohydantoin mustard on the growth delay and cell survival of 9L rat brain tumor multicellular spheroids have been investigated. Treatment with 10-25 microM concentrations of spirohydantoin mustard inhibited the growth of spheroids. Growth delay increased rapidly when assayed during the first 6-10 days after treatment, after which a decrease in delay was observed. Plots of the values for the inflection points from growth curves vs drug concentration were linear, and growth delay correlated well with cell survival. There was less growth delay caused by treating spheroids with two 10 microM concentrations of spirohydantoin mustard than with a single 20 microM concentration. When a 2 or 4 hr time interval was allowed between treatment with 10 microM concentrations of spirohydantoin mustard the delay observed was greater than that obtained with the split dose control. When the resolution of the growth delay assay is considered, the split dose effect can be explained by the existence of a 5 microM threshold before any growth delay is observed. Nonetheless, the finding that spheroids treated on the split dose protocol recover from drug damage may have implications for the design of clinical protocols.