We used the allotypic IgMa marker specific for the BCRHEL transgene in donor tumor cells to distinguish them from the IgMb expressing B cells normally present in C57BL/6 bone marrow. As illustrated in panel a of Figure 5, bone marrow from unmanipulated C57BL/6 mice did not contain IgMa expressing cells. Bone marrow from mice transplanted 28 days earlier with lymphoma cells con tained abundant tumor cells and an average of 51. 9% of the cells were positive for IgMa. The effects of L 744,832 treatment for either 28 or 7 days can be seen in Figure 5, panels c and d, respectively. the IgMa expressing tumor cells in the bone marrow were signifi cantly reduced. Even after 28 days of treatment a small, but substantial number of the transgenic B cells remained when compared to mice that did not receive a transplant.

Similar results were seen when SCH66336 was used to treat mice transplanted with mature B cell lymphomas. When we examined isolated splenocytes for expression of IgMa and B220 as markers for the lymphoma cells from the tumor transplant, we found that about 32% of the cells were positive for these two markers 18 days after transplantation. Treatment with SCH66336 for 3 days led to a statistically significant decrease in the number of tumor cells to 5% of splenocytes, although they were not completely eliminated. Sustained remissions of B cell lymphomas with brief L 744,832 treatment We next examined whether the treatment of tumor bear ing mice for 7 days with L 744,832 could cause long last ing remissions from acute B cell lymphoma.

Two separate experiments were conducted with either 5 mice or 10 mice that had received 106 tumor cells and were then treated with L 744,832 for 7 days, starting 21 days after the transplantation, when lympho mas were first evident by external examination in all trans plant recipient mice. In the first experiment, the untreated mice became moribund and were euthanized between 5 and 6 weeks after transplantation. One of the treated mice did not appear to respond to L 744,832 treatment and tumor progression was similar to untreated mice. Three of the remaining 4 treated mice showed temporary remis sions of lymphoma. There were no signs of lymphaden opathy in these mice until approximately 6 weeks after the treatment ended.

These 3 mice survived for approximately 17 weeks and developed very large, indolent lymphomas Drug_discovery that were not as aggressive as the original transplanted cells, which would be expected to cause morbidity within 3 weeks of visible lymphadenopathy. Lymphadenopathy never returned in the fifth treated mouse and it was euth anized after 52 weeks. Necropsy showed no signs of splenomegaly or lymphadenopathy. In the second experiment, the untreated tumor recipients showed visible signs of tumor at 3 weeks and had to be euthanized between 3 and 6 weeks.