Efficacy of bortezomib in a direct xenograft model of primary effusion lymphoma.
Primary effusion lymphoma (PEL) is an aggressive B-cell lymphoma most commonly diagnosed in HIV-positive patients and universally associated with Kaposi's sarcoma-associated herpesvirus (KSHV). Chemotherapy treatment of PEL yields only short-term remissions in the vast majority of patients, but efforts to develop superior therapeutic approaches have been impeded by lack of animal models that accurately mimic human disease. To address this issue, we developed a direct xenograft model, UM-PEL-1, by transferring freshly isolated human PEL cells into the peritoneal cavities of NOD/SCID mice without in vitro cell growth to avoid the changes in KSHV gene expression evident in cultured cells. We used this model to show that bortezomib induces PEL remission and extends overall survival of mice bearing lymphomatous effusions. The proapoptotic effects of bortezomib are not mediated by inhibition of the prosurvival NF-kappaB pathway or by induction of a terminal unfolded protein response. Transcriptome analysis by genomic arrays revealed that bortezomib down-regulated cell-cycle progression, DNA replication, and Myc-target genes. Furthermore, we demonstrate that in vivo treatment with either bortezomib or doxorubicin induces KSHV lytic reactivation. These reactivations were temporally distinct, and this difference may help elucidate the therapeutic window for use of antivirals concurrently with chemotherapy. Our findings show that this direct xenograft model can be used for testing novel PEL therapeutic strategies and also can provide a rational basis for evaluation of bortezomib in clinical trials.
Sarosiek
Kristopher A
KA
Department of Molecular and Cellular Pharmacology, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Cavallin
Lucas E
LE
Bhatt
Shruti
S
Toomey
Ngoc L
NL
Natkunam
Yasodha
Y
Blasini
Wilfredo
W
Gentles
Andrew J
AJ
Ramos
Juan Carlos
JC
Mesri
Enrique A
EA
Lossos
Izidore S
IS
D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002522:Chlorocebus aethiops; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D050699:E2F3 Transcription Factor / Q000378:metabolism; D017809:Fatal Outcome; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019288:Herpesvirus 8, Human / Q000187:drug effects / Q000502:physiology; D006801:Humans; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000821:virology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome; D056811:Unfolded Protein Response / Q000187:drug effects; D014709:Vero Cells; D014771:Virion / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D001897:Boronic Acids; D050699:E2F3 Transcription Factor; C490840:E2f3 protein, mouse; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D000069286:Bortezomib