We have tested farnesyl transferase inhibitors (FTIs) using a mouse model of mature B cell lymphoma to determine if these drugs may be useful in treating similar lymphoid cancers. Although FTIs were originally developed to block the activation of the Ras family of oncogenes, they are also effective in blocking the growth of tumor cells that do not contain mutations at any of the Ras alleles . By blocking the normal processing and subcellular targeting of most farnesylated proteins in the cell, FTI treatment can have many effects. This is due to the large number of farnesylated proteins present, including proteins of the Rho family that are known to mediate antigen receptor signaling in B cells. We therefore chose to test the efficacy of FTIs against our murine B cell lymphoma model, even though there is presently no evidence that activation of Ras plays a role in genesis of the tumors.
The two FTIs that we tested are L-744,832 and SCH66336 (Sarasar, lonafarnib). Developed by Merck, L-744,832 is a peptidomimetic competitive inhibitor of farnesyl transferase that blocks the binding of CAAX peptide substrates. L-744,832 has been shown to block the growth of a variety of tumor cell lines in vitro [2–4], nude mouse xenografts of human tumor cell lines , and mouse tumor models [6–11]. SCH66336 was developed by Schering Plough, completed Phase I clinical trials [12–14], and is currently in Phase II  and Phase III clinical trials. In vitro, SCH66336 has been shown to cause cell death in tumor cell lines [16–18]. Preclinical studies demonstrated that SCH66336 is orally bioavailable and could block the growth of human tumor cells in mouse xenografts  and of mouse tumor cells in transgenic models [17, 19–21]. The efficacy of L-744,832 and SCH66336 does not appear to correlate with the expression of activated Ras protein in either human or murine tumors. Although these two FTIs have been tested in other preclinical models , the efficacy of this class of drugs has not been examined in clinical trials with B cell lymphoma patients.
Certain lymphoid malignancies are sensitive to FTI treatment , suggesting that FTIs can affect the proliferation or survival signaling pathways in lymphocytes. The growth of large cleaved cell lymphomas in transgenic mice expressing an N-Ras oncogene driven by the MMTV promoter can be prevented by SCH66336 treatment . Transformed lymphocytes from T cell ALL patients activate cell death when treated with the FTI R115777 in vitro . In addition to their effects on cancer cells, FTIs have also been shown to affect normal lymphocyte signaling. T cell proliferation stimulated by antigen receptor activation can be blocked by the FTIs cinnamaldehyde  and A-228839 . The dual prenylation inhibitor, L-778,123, which blocks both farnesylation and geranylgeranylation, blocks T cell proliferation activated either by antigen receptor-stimulation or by interleukin-2 (IL-2), without affecting IL-2-mediated survival . Statins, which indirectly affect farnesylation and geranylgeranylation through mevalonate biosynthesis, are also known to have immunomodulatory effects .
We have used a mouse model in which the overexpression of the proto-oncogene c-Myc creates a breach of tolerance in B cells . The self-reactive B cells in these mice generate a mature B cell lymphoma that closely resembles Burkitt's lymphoma in humans . The mice express three transgenes: (A) the oncogene c-Myc expressed from the Eμ immunoglobulin (Ig) heavy chain promoter, (B) the pre-rearranged Ig heavy and light chains specific for hen egg lysozyme (HEL) expressed from the endogenous Ig promoter, and (C) secreted HEL expressed from a metallothionine promoter. The majority of B cells in the Eμ-Myc/BCRHEL/HEL transgenic mice express only BCRHEL IgM on their surface and are specific for the self-antigen, HEL. Tolerance to this self-antigen is overcome by the over-expression of c-Myc in these cells  and the resulting autoreactive B cells are hyperproliferative and form tumors in the lymph nodes and spleen. The lymphoma phenotype occurs in 100% of the Eμ-Myc/ BCRHEL/HEL transgenic mice with a median latency of 8 weeks . The tumors can be transplanted into unmanipulated C57BL/6 mice and the transplant recipients uniformly develop tumors after 3–4 weeks that appear identical to those in the transgenic donors. This transgenic mouse line is similar to other lymphoma models that overexpress c-Myc [31–34], except for context of overexpression, in autoreactive B cells. Antigen receptor activation may be similarly involved in tumorigenesis in certain human lymphoid malignancies .
The development of the Eμ-Myc/BCRHEL/HEL mice permits preclinical testing in this model in an effort to ascertain whether clinical trials of FTIs on mature B cell lymphomas, such as Burkitt's lymphoma, might be in order. In this report, we have demonstrated that FTIs can disrupt the growth and survival pathways in the murine tumor cells. Mice with transplanted tumors showed responses to either FTI, demonstrating effectiveness in vivo of this class of drug against this malignant B cell lymphoma. These preclinical results may have important implications for the treatment of B cell lymphomas in humans, particularly those whose proliferation or survival are dependent on antigen activation.