The new vascular disrupting agent combretastatin-A1-disodium-phosphate (OXi4503) enhances tumour response to mild hyperthermia and thermoradiosensitization.
OBJECTIVE
The aim of this study was to investigate the anti-cancer effect of the novel vascular disrupting agent (VDA), combretastatin-A1-disodium-phosphate (OXi4503), when combined with mild hyperthermia and/or radiation.


METHODS
A C3H mammary carcinoma was grown subcutaneously in the rear right foot of female CDF1 mice, and treated when a volume of 200 mm(3) was reached. OXi4503 was administered intra-peritoneally at variable doses. Hyperthermia was administered locally to the tumour-bearing foot using a thermostat-controlled water bath. Radiation treatment was performed locally using a conventional X-ray machine. Tumour response was assessed with either a tumour growth time or a tumour control assay.


RESULTS
The optimal delay between administration of 50 mg/kg of OXi4503 and hyperthermia was found to be 3 hours. The linear relationship between tumour growth time (TGT) and heating time at a specific temperature resulted in slope values between -0.003 days/min and 0.09 days/min at temperatures between 40 degrees C and 42.5 degrees C. When combined with OXi4503 this was significantly increased to 0.008 days/min and 0.03 days/min at temperatures between 39.5 degrees C and 41 degrees C, respectively. Above 41 degrees C, combined treatment did not result in significantly greater slope values. The radiation dose required to control 50% of the tumours (TCD50) was 52 Gy. Combining radiation with either heat treatment at 41.5 degrees C for 1 hour or OXi4503 reduced the TCD50 to 47 Gy and 41 Gy, respectively. Combining radiation with heat and OXi4503 further reduced the TCD50 to 37 Gy.


CONCLUSIONS
OXi4503 is a highly potent VDA, which is capable of significantly enhancing the anti-cancer effect of mild hyperthermia. Mild temperature thermoradiosensitization was also enhanced.
Department of Experimental Clinical Oncology, Aarhus University Hospital NBG, Aarhus, Denmark. hokland@mr.au.dk
S L
SL
Hokland
M R
MR
Horsman
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001808:Blood Vessels / Q000187:drug effects; D003131:Combined Modality Therapy; D011756:Diphosphates / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006979:Hyperthermia, Induced / Q000379:methods*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000628:therapy*; D051379:Mice; D013267:Stilbenes / Q000008:administration & dosage / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D011756:Diphosphates; C465018:Oxi 4503; D013267:Stilbenes