The new vascular disrupting agent combretastatin-A1-disodium-phosphate (OXi4503) enhances tumour response to mild hyperthermia and thermoradiosensitization.

Abstract

PURPOSE:

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.

MATERIALS AND 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.

• Authors: S L Hokland, M R Horsman
• Journal: International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group (Int J Hyperthermia) Vol. 23 Issue 7 Pg. 599-606 (Nov 2007) ISSN: 0265-6736 [Print] England
• PMID: 18038290 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Diphosphates
• Oxi 4503
• Stilbenes

Topics

• Animals
• Antineoplastic Agents (administration & dosage, therapeutic use)
• Blood Vessels (drug effects)
• Combined Modality Therapy
• Diphosphates (administration & dosage, therapeutic use)
• Female
• Hyperthermia, Induced (methods)
• Mammary Neoplasms, Experimental (blood supply, drug therapy, therapy)
• Mice
• Stilbenes (administration & dosage, therapeutic use)