Vascular targeting agent Oxi4503 inhibits tumor growth in a colorectal liver metastases model.
OBJECTIVE
Oxi4503 is a potent vascular targeting agent belonging to the family of combretastatins. These agents produce an acute reduction in tumor blood flow leading to tumor necrosis. Despite evidence of its efficacy in certain malignancies, the effect on colorectal liver metastases remains largely unknown. This study investigates the effect of Oxi4503 on colorectal liver metastases in a murine model.


METHODS
The effect of a single dose of Oxi4503 on established tumors in a murine model of colorectal liver metastases was assessed following administration of 1-50 mg/kg Oxi4503. In addition, the effects of continuous, daily and intermittent dosing (1-5 mg/kg) on tumor necrosis and growth were studied by quantitative histological and stereological analysis. The effect of multiple dosing on long-term survival was also assessed using the Kaplan-Meier analysis. The microvascular effects of therapy were studied by scanning electron microscopy of microvascular resin casts.


RESULTS
A single dose of 5 or 50 mg/kg of Oxi4503 produced significant tumor necrosis compared to the controls. Subcutaneous continuous dosing infusion with Oxi4503 at 1 mg/kg/day reduced tumor growth compared to the controls, but was associated with marked systemic toxicity. Daily administration over 21 days was associated with significant mortality. Intermittent dosing of Oxi4503 (two doses, 3 days apart) produced the greatest reduction in tumor growth with minimal toxicity and conferred a significant survival advantage. Microvascular casts demonstrated significant disruption of tumor vessels.


CONCLUSIONS
A single dose of Oxi4503 produced significant necrosis and microvascular injury in colorectal liver metastases. Intermittent dosing with Oxi4503 produced the maximum reduction in tumor growth, minimal toxicity, and a significant improvement in survival. Oxi4503 is a potential anticancer agent. Further research into its mechanism of action and its synergistic use with other therapies is warranted.
Malcontenti-Wilson
Caterina
C
Department of Surgery, Austin Hospital, University of Melbourne, Melbourne, Victoria, Australia. surgery-armc@unimelb.edu.au
Chan
Lisa
L
Nikfarjam
Mehrdad
M
Muralidharan
Vijayaragavan
V
Christophi
Christopher
C
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D011756:Diphosphates / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015918:Infusion Pumps, Implantable; D007263:Infusions, Parenteral; D007274:Injections, Intraperitoneal; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008833:Microcirculation / Q000187:drug effects / Q000473:pathology; D009336:Necrosis; D012039:Regional Blood Flow / Q000187:drug effects; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors
D000970:Antineoplastic Agents; D011756:Diphosphates; C465018:Oxi 4503; D013267:Stilbenes