Skip to main content
. 2006 Dec 1;116(12):3277–3291. doi: 10.1172/JCI29314

Figure 5. The vascular disrupting agent CA4P targets bone marrow microvascular sinusoids as well as megakaryopoiesis.

Figure 5

(A) CA4P delays platelet recovery and blocks rebound thrombocytosis. TSP-DKO mice were treated with 250 mg/kg 5-FU i.v. and either with an additional low dose of CA4P (25 mg/kg) every other day or with PBS. CA4P has not been shown to be myelosuppressive at this dose in long-term studies (data not shown). While 5-FU alone resulted in a typical rebound thrombocytosis, CA4P-treated mice reverted back to normal platelet levels later, and the rebound effect was completely abrogated. n = 5 in each group. P < 0.02 on day 13. (B) CA4P delays white blood cell recovery. Total peripheral blood white cell counts displayed a lower nadir and a delayed recovery albeit with a marked rebound effect that is rather atypical for white cells. (C) CA4P increases severity of anemia but does not delay red blood cell recovery. Hemoglobin levels were decreased to lower absolute levels when CA4P was added to the myelosuppressive regimen, but the overall time course of rbc regeneration was comparable to that in the group that received 5-FU only. (D) Histological analysis of the marrow on day 10 revealed that the repopulation of the marrow with hematopoietic cells was not significantly inhibited. However, the vascular microarchitecture was severely disturbed, resulting in areas of hemorrhage (black arrows). H&E staining was used. Original magnification, ×400. (E) Staining with the panendothelial cell marker antibody MECA32 showed disrupted, leaky microvasculature in the CA4P-treated mice (red arrows). DAB was counterstained with hematoxylin. Original magnification, ×400. (F) The same femurs as in D were stained with anti-citrulline antibody to identify megakaryocytes. Interestingly, it became evident that the vascular disruption seen with CA4P treatment resulted in a selective defect in megakaryocyte repopulation of the marrow, with a reversion of the TSP-DKO phenotype toward normal. Anti-citrulline staining with DAB was counterstained with hematoxylin. Original magnification, ×400.