E- em Myc /em transgenic mice that overexpress em c-Myc /em in B cells after the Pre/Pro-B cell stage of development [53] were from The Jackson Laboratory (Pub Harbor, ME)

E- em Myc /em transgenic mice that overexpress em c-Myc /em in B cells after the Pre/Pro-B cell stage of development [53] were from The Jackson Laboratory (Pub Harbor, ME). degree than na?ve B cells stimulated with antigen. In syngeneic mice transplanted GSK4716 with the transgenic lymphoma cells, L-744,832 treatment prevented the growth of the tumor cells and the morbidity associated with the producing lymphoma progression. Tumors that arose from transplantation of the lymphoma cells regressed with as little as three days of treatment with L-744,832 or “type”:”entrez-protein”,”attrs”:”text”:”SCH66336″,”term_id”:”1052737610″,”term_text”:”SCH66336″SCH66336. Treatment of these founded lymphomas with L-744,832 for seven days led to long-term remission of the disease in approximately 25% of animals. Summary FTI treatment can block the proliferation and survival of self-reactive transformed B cells that overexpress em Myc /em . In mice transplanted with mature B cell lymphomas, we found that FTI treatment led to regression of disease. FTIs warrant further consideration as restorative agents for adult B cell lymphomas and additional lymphoid tumors. Background We have tested farnesyl transferase inhibitors (FTIs) using a mouse model of adult B cell lymphoma to determine if these drugs may be useful in treating similar Rabbit Polyclonal to MB lymphoid cancers. Although FTIs were originally developed to block the activation of the Ras family of oncogenes, they are also effective in obstructing the growth of tumor cells that do not contain mutations at any of the em Ras /em alleles [1]. By obstructing the normal control and subcellular focusing on 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 consequently chose to test the effectiveness 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 “type”:”entrez-protein”,”attrs”:”text”:”SCH66336″,”term_id”:”1052737610″,”term_text”:”SCH66336″SCH66336 (Sarasar, lonafarnib). Developed by Merck, L-744,832 is definitely a peptidomimetic competitive inhibitor of farnesyl transferase that blocks the binding of CAAX peptide substrates. L-744,832 offers been shown to block the growth of a variety of tumor cell lines em in vitro /em [2-4], nude mouse xenografts of human being tumor cell lines [5], and mouse tumor models [6-11]. “type”:”entrez-protein”,”attrs”:”text”:”SCH66336″,”term_id”:”1052737610″,”term_text”:”SCH66336″SCH66336 was developed by Schering Plough, completed Phase I medical tests [12-14], and is currently in Phase II [15] and Phase III clinical tests. em In vitro /em , “type”:”entrez-protein”,”attrs”:”text”:”SCH66336″,”term_id”:”1052737610″,”term_text”:”SCH66336″SCH66336 GSK4716 has been shown to cause cell death in tumor cell lines [16-18]. Preclinical studies demonstrated that “type”:”entrez-protein”,”attrs”:”text”:”SCH66336″,”term_id”:”1052737610″,”term_text”:”SCH66336″SCH66336 is definitely orally bioavailable and could block the growth of human being tumor cells in mouse xenografts [19] and of mouse tumor cells in transgenic models [17,19-21]. The effectiveness of L-744,832 and “type”:”entrez-protein”,”attrs”:”text”:”SCH66336″,”term_id”:”1052737610″,”term_text”:”SCH66336″SCH66336 does not appear to correlate with the manifestation of triggered Ras protein in either GSK4716 human being or murine tumors. Although these two FTIs have been tested in additional preclinical models [22], the effectiveness of this class of drugs has not been examined in medical tests with B cell lymphoma individuals. Certain lymphoid malignancies are sensitive to FTI treatment [23], suggesting that FTIs can affect the GSK4716 proliferation or survival signaling pathways in lymphocytes. The growth of large cleaved cell lymphomas in transgenic mice expressing an em N-Ras /em oncogene driven from the MMTV promoter can be prevented by “type”:”entrez-protein”,”attrs”:”text”:”SCH66336″,”term_id”:”1052737610″,”term_text”:”SCH66336″SCH66336 treatment [8]. Transformed lymphocytes from T cell ALL individuals activate cell death when treated with the FTI R115777 em in vitro /em [24]. In addition to their effects on malignancy cells, FTIs have also been shown to impact normal lymphocyte signaling. T cell proliferation stimulated by antigen receptor activation can be blocked from the FTIs cinnamaldehyde [25] and A-228839 [26]. 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 influencing IL-2-mediated survival [27]. Statins, which indirectly impact farnesylation and geranylgeranylation through mevalonate biosynthesis, are also known to have immunomodulatory effects [28]. We have used a mouse model in which the overexpression of the proto-oncogene em c-Myc /em creates a breach of tolerance in B cells [29]. The self-reactive B cells in these mice generate a mature B cell lymphoma that closely resembles Burkitt’s lymphoma in humans [30]. The mice communicate three transgenes: (A) the oncogene em c-Myc /em indicated from your E immunoglobulin (Ig) weighty chain promoter, (B) the pre-rearranged Ig weighty and light chains specific for hen egg lysozyme (HEL) indicated from your endogenous Ig promoter, and (C) secreted HEL indicated from a metallothionine promoter. The majority of B cells in the E- em Myc /em /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 definitely overcome from the over-expression of em c-Myc /em in these cells [29] and the producing autoreactive B cells are hyperproliferative and form tumors in the lymph nodes and spleen. The lymphoma phenotype happens in 100% of the GSK4716 E- em Myc/ /em BCRHEL/HEL transgenic mice having a median latency of 8 weeks [30]. The tumors can be transplanted into.