For four separate experiments, lym phoma cells were freshly isolated from the lymph nodes and spleen of an EMyc/BCRHEL/HEL transgenic mouse and 106 cells were transplanted into each of a cohort of C57BL/6 recipients. Figure 2A shows, for one of the exper iments, the number of spleen cells isolated from mice that were transplanted with 106 tumor cells 28 days earlier or C57BL/6 mice that had not received tumor cells. Flow cytometry confirmed that the additional cells in the spleen were activated B cells that express BCRHEL on their surface. These observations indicate that the transplanted cells have formed lymphomas in the recipient mice. In this experiment, four mice in each group were treated once daily with 625 g of L 744,832 intrave nously starting the day after tumor transplantation and four mice were left untreated.

Daily administration of L 744,832 prevented the transplanted tumors from causing splenomegaly in recipient mice. Treatment of the wild type mice also resulted in a small, but significant, decrease in the number of isolated splenocytes and the numbers of viable cells isolated are similar for the two groups of FTI treated mice. Figures 2B and 2C show the results from a separate exper iment where the recipients were not treated immediately after transplantation of the tumor. Transplant recipients either were treated for 7 days beginning 21 days after transplantation, when enlarged lymph nodes were visible upon external examination, or were treated for 3 days beginning 24 days after transplantation, when the mice were beginning to show debilitation due to the lymphomas.

The mice were then treated with L 744,832 as above, or left untreated, for comparison. The Anacetrapib administration of L 744,832 for either 7 or 3 days caused a large reduction in the size of the spleen, as well as the lymph nodes and thymi and a corresponding drop in the number of cells isolated from the spleen. The treated mice became more active and resumed grooming behavior within two days of the start of treatment. Similar results were observed in all four experiments using L 744,832. Together, these experi ments show that L 744,832 can prevent mature B cell lym Treatment of lymphoma bearing mice with L 744,832 phomas from becoming established in mice and can cause established tumors to regress. Efficacy of SCH66336 in vivo We wanted to see if a distinct FTI, SCH66336, could have similar effects on the B cell lymphoma model.

In three separate experiments, which all yielded similar results, we transplanted 106 transgenic tumor cells into a cohort of C57BL/6 recipients. Approximately 2 weeks after trans plantation, some of the mice were treated by oral gavage with 1. 56 mg SCH66336 or with vehicle every 12 hours. After 3 days of treatment, the mice were euthanized and splenocytes were isolated for analysis.