The two FTIs that we tested are L 744,832 and SCH66336. Developed by Merck, L 744,832 is a peptidomimetic competitive inhibitor of farnesyl trans ferase that blocks the binding of CAAX peptide substrates. L 744,832 has been shown to block the growth of a vari ety of tumor cell lines in vitro, nude mouse xenografts of human tumor cell lines, and mouse tumor models. SCH66336 was developed by Scher ing Plough, completed Phase I clinical trials, 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. 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.

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 mod els, 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 treat ment, 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 acti vate 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 activa tion can be blocked by the FTIs cinnamaldehyde and A 228839. The dual prenylation inhibitor, L 778,123, which blocks both farnesylation and geranylger anylation, blocks T cell proliferation activated either by antigen receptor stimulation or by interleukin 2, without affecting IL 2 mediated survival. Statins, which indirectly affect farnesylation AV-951 and geranylgeranyla tion 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 gen erate a mature B cell lymphoma that closely resembles Burkitts lymphoma in humans. The mice express three transgenes the oncogene c Myc expressed from the Eimmunoglobulin heavy chain promoter, the pre rearranged Ig heavy and light chains specific for hen egg lysozyme expressed from the endogenous Ig promoter, and secreted HEL expressed from a met allothionine promoter.