Alkyl phospholipid perifosine induces myeloid hyperplasia in a murine myeloma model.
OBJECTIVE
Alkyl-lysophospholipids are a novel class of antitumor agents. Perifosine is a novel alkyl-lysophospholipid that can induce apoptosis in multiple myeloma (MM) tumor cells, both in vitro and in vivo. We investigated the effects of perifosine on the peripheral blood, bone marrow, and spleen of mice inoculated with subcutaneous plasmacytomas.


METHODS
Immunocompromised mice were inoculated with myeloma cell lines and treated with oral perifosine in either a daily or weekly schedule, or with vehicle only. When plasmacytomas reached 2 cm, mice were sacrificed. Terminal blood was analyzed with a Coulter counter, and counts were confirmed by light microscopy. Marrow and spleen were also analyzed by light microscopy.


RESULTS
In control mice, mean hemoglobin was 12 g/dL, white blood cell (WBC) count 7 x 10(9)/L, and mean platelet count was 292 x 10(9)/L. In contrast, the respective values for mice treated with perifosine weekly were 11 g/dL, 9 x 10(9)/L, and 944 x 10(9)/L; and for mice treated with perifosine daily were 10 g/dL, 11 x 10(9)/L, and 752 x 10(9)/L. The increase in WBCs was due, predominantly, to a neutrophilia. Compared to control mice, perifosine treatment induced marrow hypercellularity and splenic white pulp expansion.


CONCLUSIONS
These findings have clinical relevance because myeloid suppression is a dose-limiting toxicity of many cytotoxic agents, and myeloid hyperplasia is usually only observed in the setting of growth factor stimulation. Coupled with its remarkable in vitro MM cytotoxicity, these results strongly support the use of perifosine in clinical trials for patients with MM.
Catley
Laurence
L
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Mass., USA. laurence.catley@mater.org.au
Hideshima
Teru
T
Chauhan
Dharminder
D
Neri
Paola
P
Tassone
Pierfrancesco
P
Bronson
Roderick
R
Song
Weihua
W
Tai
Yu-Tzu
YT
Munshi
Nikhil C
NC
Anderson
Kenneth C
KC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D006965:Hyperplasia; D007964:Leukocytosis / Q000139:chemically induced; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology*; D022423:Myeloid Cells / Q000187:drug effects* / Q000473:pathology; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013922:Thrombocytosis / Q000139:chemically induced
D010767:Phosphorylcholine; C105905:perifosine