Liposomal vincristine for the treatment of human acute lymphoblastic leukaemia in severe combined immunodeficient (SCID) mice.
Non-obese diabetic NOD/SCID mice have been used to grow human leukaemia as a systemic disease. The animals were inoculated with leukaemic cells obtained from a 36-year-old male with early B-cell precursor acute lymphoblastic leukaemia and on day 15 were given the first of three weekly injections of 1 mg/kg vincristine or equimolar liposomal vincristine. The development of leukaemia in the mice was monitored by taking weekly blood samples and measuring the cell content by flow cytometry. The median time to 50% human cells in the peripheral blood of mice treated with free vincristine was 41 d from the start of treatment compared with 49 d for mice treated with liposomal vincristine (P < 0.01). The median day of death for mice treated with free vincristine was 47 d from the start of treatment and 57 d for mice receiving liposomal vincristine (P<0.01), thus providing a 21% increase in lifespan for animals treated with the liposomal preparation. There was slightly greater weight loss in mice treated with free vincristine than those given liposomal vincristine. Measurement of in vitro colony forming bone marrow progenitor cells in similarly treated, tumour-free mice, showed no difference in progenitor cell survival between mice that received either type of vincristine. We conclude that encapsulating vincristine in liposomes improves the therapeutic index of this drug measured in mice bearing human leukaemia. This may lead to use of the drug in conventional combination chemotherapy with greater safety or, in this setting, at higher dosage.
Academic Department of Haematology and Cytogenetics, Institute of Cancer Research, Sutton, Surrey, UK.
J L
JL
Millar
B C
BC
Millar
R L
RL
Powles
J P
JP
Steele
R D
RD
Clutterbuck
P L
PL
Mitchell
G
G
Cox
E
E
Forssen
D
D
Catovsky
D000328:Adult; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects; D006801:Humans; D008081:Liposomes; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D016019:Survival Analysis; D014750:Vincristine / Q000008:administration & dosage / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D008081:Liposomes; D014750:Vincristine