The hypertensive effect of combretastatin and the possible implications for therapy Free

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Introduction: Clinical studies with combretastatin A-4 disodium phosphate (CA4DP) indicate that it can induce hypertension, which could not only lead to unwanted side-effects, but may also reduce anti-tumor efficacy. The aim of this study was to use a mouse model to investigate the potential of CA4DP to induce hypertension and whether this could influence the interaction with radiation.

Material and Methods: Female CDF1 mice were used in all experiments, and were either non-tumor bearing or had a 200 cubic mm C3H mammary carcinoma growing in the right rear foot. CA4DP was dissolved in saline and injected intraperitoneally at 0.02 ml/g mouse body weight. Mean arterial blood pressure (MABP) was measured following cannulation of the carotid artery of non-tumor bearing mice. After cannulation the animals were allowed to recover before being transferred to special restraining jigs that enabled measurements on non-anaesthetized animals. MABP was determined by connecting the cannula to a pressure transducer, and values obtained before and up to 6-hours after injecting CA4DP. Tumor bearing animals were also restrained in jigs and the C3H mammary carcinoma locally irradiated (240 kV x-rays) with single graded radiation doses and the percentage of mice in each treatment group showing local control at 90 days, recorded. TCD50 values (the radiation dose producing local control in 50% of treated animals) were estimated from full radiation dose response curves. Statistical analysis was performed with a Chi-squared test (TCD50) or Student’s t-test (MABP), with the significance level being p<0.05.

Results: The TCD50 value (with 95% confidence interval) for tumors given radiation alone was 53 Gy (51-55). Irradiating tumors and then injecting CA4DP (25 mg/kg) 30 minutes later significantly enhanced the tumor radiation response, with a TCD50 value of 48 Gy (45-51) being obtained. However, a 100 mg/kg dose of CA4DP was less effective with a non-significant decrease to 50 Gy (46-54). When the CA4DP dose was increased to 250 mg/kg the TCD50 again significantly decreased to 46 Gy (42-50). Initial measurements of MABP showed a mean value (+/- 1 S.E.) of 136 mmHg (131-142) in control mice, which was significantly increased to 170 mmHg (163 - 177) within 1-hour after injecting 100 mg/kg CA4DP, and was maintained at this level for at least 6-hours. Additional MABP experiments are in progress with all drug doses as used in the radiation studies, to see if a dose response relationship exists.

Conclusions: Our preliminary measurements of MABP showed a clear CA4DP-induced hypertension in our CDF1 mice with a 100 mg/kg dose. This increase in MABP may explain the partial loss of efficacy, with this drug dose, for enhancing radiation damage in the C3H mammary carcinoma.Supported by a grant from the Danish Cancer Society.