Farnesyl transferase inhibitors induce extended remissions in transgenic mice with mature B cell lymphomas.
BACKGROUND
We have used a mouse model based on overexpression of c-Myc in B cells genetically engineered to be self-reactive to test the hypothesis that farnesyl transferase inhibitors (FTIs) can effectively treat mature B cell lymphomas. FTIs are undergoing clinical trials to treat both lymphoid and non-lymphoid malignancies and we wished to obtain evidence to support the inclusion of B cell lymphomas in future trials.


RESULTS
We report that two FTIs, L-744,832 and SCH66336, blocked the growth of mature B cell lymphoma cells in vitro and in vivo. The FTI treatment affected the proliferation and survival of the transformed B cells to a greater extent than naïve B cells stimulated with antigen. In syngeneic mice transplanted with the transgenic lymphoma cells, L-744,832 treatment prevented the growth of the tumor cells and the morbidity associated with the resulting 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 SCH66336. Treatment of these established lymphomas with L-744,832 for seven days led to long-term remission of the disease in approximately 25% of animals.


CONCLUSIONS
FTI treatment can block the proliferation and survival of self-reactive transformed B cells that overexpress Myc. In mice transplanted with mature B cell lymphomas, we found that FTI treatment led to regression of disease. FTIs warrant further consideration as therapeutic agents for mature B cell lymphomas and other lymphoid tumors.
Field
Kenneth A
KA
Cell Biology and Biochemistry Program, Biology Department, Bucknell University, Lewisburg, PA, USA. kfield@bucknell.edu
Charoenthongtrakul
Soratree
S
Bishop
J Michael
JM
Refaeli
Yosef
Y
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005434:Flow Cytometry; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012074:Remission Induction; D003986:Dibenzocycloheptenes
D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D008715:Methionine; D010880:Piperidines; D011725:Pyridines; C096898:L 744832; C115354:lonafarnib; D003986:Dibenzocycloheptenes