Growth retardation and depigmentation of hair after high-dose busulfan and congenic hematopoietic cell transplantation in mice.
Busulfan, a myeloablative but non-immunosuppressive alkylating agent, is used extensively in clinical bone marrow transplantation (BMT), but the effects of high-dose administration have not been previously evaluated in preclinical BMT settings with young murine recipients. We compared the survival and growth of C57BL/6 mice given graded single doses of busulfan (10-100 mg/kg) or total body irradiation (TBI; 900 cGy) at age 9 days and hematopoietic cell transplantation (HCT; transplantation of congenic bone marrow and spleen cells) 24 h later. The 30-day survival was 87-100% in mice transplanted after 10-40 mg/kg busulfan and 79% after TBI, but fell to 54% and 33%, respectively, after 80 mg/kg and 100 mg/kg busulfan, suggesting that this latter dosage range represents the LD50 for single-dose busulfan in young C57BL/6 mice given stem cell rescue. The weights of 10-week-old mice given HCT after lower doses of busulfan ranged from 87% of control at 10 mg/kg to 64-69% of control in mice conditioned with 35-65 mg/kg busulfan or TBI. Impairment of weight gain was most striking (approximately 50% of control) in mice transplanted after 80-100 mg/kg busulfan. Despite retardation of somatic growth, the brain weights of busulfan-conditioned mice remained at least 90% of control, and there were no obvious neuropathological alterations in the brains of these animals. All mice treated with at least 20 mg/kg busulfan or TBI lost hair by 3-4 weeks after transplant.(ABSTRACT TRUNCATED AT 250 WORDS)
Oncology Center, Johns Hopkins University School of Medicine, Baltimore.
A M
AM
Yeager
C
C
Shinn
E R
ER
Farmer
J R
JR
Wingard
M J
MJ
Yeager
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002066:Busulfan / Q000008:administration & dosage / Q000633:toxicity*; D006130:Growth Disorders / Q000209:etiology*; D006200:Hair Color / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation; D007928:Lethal Dose 50; D051379:Mice; D008810:Mice, Inbred C57BL; D010859:Pigmentation Disorders / Q000209:etiology*
D002066:Busulfan