A review and update of the current status of the vasculature-disabling agent combretastatin-A4 phosphate (CA4P)

Abstract

Vascular-disrupting strategies impair a tumor's blood vessel network, which is essential for tumor progression and metastasis. Vascular-disrupting agents (VDAs) cause a rapid and selective vascular shutdown in tumors to produce extensive secondary neoplastic cell death due to ischemia. A lead agent in this therapeutic strategy is the tubulin depolymerizing agent combretastatin-A4 phosphate (CA4P). Used alone, CA4P induces extensive necrosis in a wide variety of preclinical cancer models and significant blood flow reductions in the patient tumors. Preclinical and clinical data further indicate that CA4P can effectively be combined with chemotherapy or radiotherapy. Finally, the potential of combining VDAs with antiangiogenic therapies has shown considerable promise in preclinical models and such combinations are now beginning to be evaluated in patients.

Figure 1

Molecular structure of CA4P.tris

Figure 2

Histological assessment of CaNT tumours that were evaluated at various times after treatment with a 100 mg/kg dose of CA4P. a) Untreated control, b) – d) 1, 3, and 4 days post CA4P exposure, respectively. Figure was modified from (21).

Figure 3

Effect of CA4P treatment alone or in combination with Avastin on renal cell carcinoma (Caki-1) xenograft growth. CA4P (100 mg/kg) was given Mondays, Wednesdays, and Fridays for 2 weeks. Avastin treatment (2 mg/kg) was administered daily (Monday through Friday) for 2 weeks. Data shown are a) the growth of the median tumors and b) the median, 75th, and 90th percentiles of responses of tumors treated at a starting size of 200 mm3. Results in mice treated with combination therapy were significantly greater than those obtained in mice treated only with a single therapy (p<0.05, Wilcoxon rank sum test). Figure was modified from (36).