A farnesyltransferase inhibitor increases survival of mice with very advanced stage acute lymphoblastic leukemia/lymphoma caused by P190 Bcr/Abl.
Treatment of chronic myelogenous leukemia with a specific inhibitor of the Bcr/Abl tyrosine kinase, imatinib, has shown great promise. However, acute lymphoblastic leukemias that express Bcr/Abl only transiently respond to imatinib. Therefore, alternative treatments for this type of leukemia are urgently needed. Here, we examined the activity of the farnesyltransferase inhibitor SCH66336 as a single chemotherapeutic agent in a nude mouse model representative of very advanced stage Bcr/Abl P190-positive lymphoblastic leukemia/lymphoma. Our results show that oral administration of the inhibitor was able to significantly increase the survival of these mice compared to controls treated with vehicle (P<0.005), and caused marked regression of the tumor burden in the treated mice. Upon prolonged treatment, lymphomas re-emerged and a subset of cells from two of such lymphomas tested was able to survive in the presence of increased concentrations of SCH66336. The same cells, however, remained sensitive towards imatinib. A combination of the two drugs, preceded by a therapy to reduce the initial tumor burden, could be very effective in the treatment of Ph-positive ALL. We conclude that SCH66336, on its own, is remarkably effective in eradicating large numbers of lymphoblastic lymphoma cells and causing visible reduction in tumor size, with minimal toxicity.
Mishra
S
S
Division of Hematology/Oncology, Section of Molecular Carcinogenesis, Childrens Hospital of Los Angeles Research Institute, Los Angeles, CA 90027, USA.
Zhang
B
B
Groffen
J
J
Heisterkamp
N
N
D000284:Administration, Oral; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides; D004195:Disease Models, Animal; D051231:Farnesyltranstransferase; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D000068877:Imatinib Mesylate; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008819:Mice, Nude; D008822:Mice, Transgenic; D010879:Piperazines / Q000627:therapeutic use; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use; D015996:Survival Rate; D014407:Tumor Cells, Cultured / Q000637:transplantation; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D000970:Antineoplastic Agents; D001549:Benzamides; D051231:Farnesyltranstransferase; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D010879:Piperazines; D010880:Piperidines; D011505:Protein-Tyrosine Kinases; D011725:Pyridines; D011743:Pyrimidines; C115354:lonafarnib; D003986:Dibenzocycloheptenes