Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia.
Despite advances in the treatment of acute lymphoblastic leukemia (ALL), the majority of children who relapse still die of ALL. Therefore, the development of more potent but less toxic drugs for the treatment of ALL is imperative. We investigated the effects of the mammalian target of rapamycin inhibitor, RAD001 (Everolimus), in a nonobese diabetic/severe combined immunodeficiency model of human childhood B-cell progenitor ALL. RAD001 treatment of established disease increased the median survival of mice from 21.3 days to 42.3 days (P < .02). RAD001 together with vincristine significantly increased survival compared with either treatment alone (P < .02). RAD001 induced a cell-cycle arrest in the G(0/1) phase with associated dephosphorylation of the retinoblastoma protein, and reduced levels of cyclin-dependent kinases 4 and 6. Ultrastructure analysis demonstrated the presence of autophagy and limited apoptosis in cells of RAD001-treated animals. In contrast, cleaved poly(ADP-ribose) polymerase suggested apoptosis in cells from animals treated with vincristine or the combination of RAD001 and vincristine, but not in those receiving RAD001 alone. In conclusion, we have demonstrated activity of RAD001 in an in vivo leukemia model supporting further clinical development of target of rapamycin inhibitors for the treatment of patients with ALL.
Crazzolara
Roman
R
Westmead Institute for Cancer Research, Westmead Millennium, University of Sydney, Westmead, Australia.
Cisterne
Adam
A
Thien
Marilyn
M
Hewson
John
J
Baraz
Rana
R
Bradstock
Kenneth F
KF
Bendall
Linda J
LJ
D000293:Adolescent; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004357:Drug Synergism; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010919:Placebos; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016019:Survival Analysis; D014750:Vincristine / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
D010919:Placebos; D014750:Vincristine; D000068338:Everolimus; D020123:Sirolimus