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Changes in physiological blood parameters induced by combretastatin and the implication for systemic toxicity

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Targeting the tumour vasculature is a therapeutic approach currently in clinical testing. The lead vascular damaging agent is combretastatin A-4 disodium phosphate (CA4DP). Preliminary testing of CA4DP have shown efficacy but cardiovascular related systemic toxicity. Following treatment of mice with CA4DP we observed an increase in blood viscosity. We hypothesize that this could be part of the systemic toxicity effect mediated by CA4DP. Therefore, we analysed the effect of CA4DP on physiological blood parameters in both mice and rats. Materials and methods.

Blood samples were taken from the sub-orbital sinus in non-tumour bearing male CDF-1 mice and from the femoral artery in anaesthetized male wistar rats at various times following treatment with a range of CA4DP doses. Hematocrit was measured using a Hettich hematocrit centrifuge and physiological blood gas parameters such as total hemoglobin, oxygen capacity and pH were determined using an ABL520. A Student's t-test was used for statistical analysis and P<0.05 was considered to indicate a significant difference. Results.

In control mice the mean (±1S.E) hematocrit was 48.2±0.3. Following treatment with 250 mg/kg CA4DP hematocrit significantly increased to 54.8±0.4 within 2 h, remained at this level for further 6 hours and returned to normal after 12 h. For lower CA4DP doses (10 mg/kg, 25 mg/kg, and 100 mg/kg) the peak level of hematocrit was similar. The return to normal was, however, faster; 3 h for 10 mg/kg and 8 h for 25 mg/kg and 100 mg/kg. We obtained corresponding results for total hemaglobin and oxygen capacity. In rats we also observed a significant increase in hematocrit following CA4DP (30 mg/kg) treatment; in controls hematocrit was 45.3±1.4 increasing to 54.5±1.3 at 1 h. Again we obtained similar results in total hemoglobin and oxygen capacity. Conclusions.

CA4DP induced a rapid and significant increase in hematocrit in both mice and rats. The peak level obtained was independent of CA4DP dose, but the recovery was dose-dependent. This increase in hematocrit and corresponding bloodgas parameters may be part of the cardiovascular related systemic toxicity.
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Document Type: Abstract

Publication date: May 1, 2008

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