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


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.
Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark. morten@oncology.dk
Morten
M
Busk
Anja Bille
AB
Bohn
Marianne
M
Skals
Tobias
T
Wang
Michael R
MR
Horsman
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use* / Q000633:toxicity; D001794:Blood Pressure; D003131:Combined Modality Therapy; D005260:Female; D006400:Hematocrit; D006454:Hemoglobins / Q000032:analysis; D006830:Hydralazine / Q000627:therapeutic use; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D013267:Stilbenes / Q000627:therapeutic use* / Q000633:toxicity
D000959:Antihypertensive Agents; D000972:Antineoplastic Agents, Phytogenic; D006454:Hemoglobins; D013267:Stilbenes; D006830:Hydralazine; C058728:fosbretabulin