DYNAMICS OF TUMOR-CELL CLONOGEN REPOPULATION IN A MURINE SARCOMA TREATED WITH CYCLOPHOSPHAMIDE

Experiments were performed to establish the extent and kinetics of tum or cell repopulation in a murine sarcoma, designated SA-NH, treated wi th cyclophosphamide (CY). Mice bearing 8-mm leg tumors were treated wi th 200 mg/kg CY which caused a transient tumor regression. Changes in the absolute clonogen content of tumors was determined by the change i n TCD50 values (50% tumor control) obtained under hypoxic conditions o f local tumor irradiation at different times after CY treatment until tumors regrew to the pretreatment size. For comparison, hypoxic TCD50 values were determined during the growth of tumors not treated with CY . CY greatly depleted tumors of clonogenic cells as manifested by the reduction in the control TCD50 value of 64.5 Gy to 32.8 Gy 1 day after CY treatment. The reduced TCD50 value remained unchanged for 2 weeks after treatment with CY, at which time the TCD50 began to rapidly incr ease, continuing until the end of the observation period of 21 days wh en tumors reached the pretreatment size. In contrast, there was a cons tant but slower increase in TCD50 values during the growth of tumors n ot treated with CY. The daily increase in TCD50 was more than twice as high in CY-treated than in CY-untreated tumors: 4.5 Gy/day versus 2.1 Gy/day. This implies that the rate of clonogen production in CY-treat ed tumors was twice as high as that of unperturbed tumors. The possibi lity that tumors regrowing after CY treatment might consist of cells c ross-resistant to irradiation was rejected by experiments showing that tumors grown from cells taken from CY-recurrent tumors were not signi ficantly more resistant than control tumors of the same size. Further studies revealed that systemic effects produced by CY are conducive to tumor cell proliferation but the contribution of this mechanism to th e observed increased rate of tumor cell repopulation in the recurrent tumors is uncertain.