Combretastatin-induced hypertension and the consequences for its combination with other therapies

Abstract

Purpose: Combretastatin A-4 phosphate (CA4P) is a promising vascular disrupting agent in cancer treatment, but elicits hypertension in patients. The aim of this study was to use a mouse model to investigate whether hypertension or its modification influenced the treatment efficacy of CA4P in combination with other therapies.

Material and methods: C3H mammary carcinoma bearing or non-bearing CDF1 mice were used. The effects of CA4P alone or in combination with the antihypertensive drug hydralazine (HDZ) on mean arterial blood pressure (MABP), hematocrit (Hct) and hemoglobin concentration ([Hb]) were characterized in non-tumor-bearing animals. Tumor-bearing mice were also treated locally with radiation and/or hyperthermia (41.5 ° C; 60 min) in combination with CA4P alone or CA4P plus HDZ, and TCD50 values (radiation dose that controls 50% of tumors) determined.

Results: Hct, [Hb] and MABP respectively increased from 49.3 ± 0.3%, 9.1 ± 0.1mM and 110 ± 7 mm Hg, to 54.7 ± 0.2%, 10.3 ± 0.1 mM and 127 ± 5 mm Hg, within 1h after injecting 100 mg/kg CA4P. For each parameter the magnitude of the peak increase was largely dose independent within the CA4P dose range tested (10-250 mg/kg). However, high CA4P doses delayed the return to baseline and Hct and [Hb] recovered more slowly than MABP. Co-administration of HDZ (0.2mg/kg) was able to suppress the CA4P-induced increase in MABP for several hours but did not noticeably affect the changes in Hct and [Hb]. The TCD50 value (± 95% confidence interval) for radiation alone was 53 (51-55) Gy. Tumor irradiation followed by injection of either CA4P (100 mg/kg) or CA4P+HDZ 30 min later reduced the TCD50 values to 50 (46-54) Gy and 48 (45-52) Gy, respectively. Heating tumors after irradiating further decreased the TCD50 value to 46 (43-48) Gy. When all treatments were combined the TCD50 was 35 (32-38) Gy, regardless of whether the drugs were CA4P or CA4P+HDZ.

Conclusions: CA4P significantly increased Hct, [Hb] and MABP. Hypertension, but not increases in Hct and [Hb], could be reversed with the antihypertensive drug HDZ. CA4P significantly improved tumor response to radiation or thermoradiation, neither of which was influenced by the addition of HDZ.