Bevacizumab, a vascular endothelial growth factor (VEGF) specific antibody reduces interstitial fluid pressure (IFP) in human rectal cancer xenograft (HT29) by day 5: Is this evidence for rescheduling its timing relative to chemotherapy?

Abstract

4043 Background: Interstitial fluid pressure (IFP) of most solid tumours is increased relative to normal tissues; this is thought to be associated with the development of structurally and functionally abnormal blood and lymphatic vessels and interstitial fibrosis. Such interstitial hypertension creates a barrier for tumour transvascular transport, consequently compromising the delivery and efficacy of chemotherapy. We investigated the effect of Bevacizumab on IFP of a human rectal cancer xenograft. Methods: SCID mice bearing subcutaneous HT29 tumours of =8.5 mm diameter received a single dose of 10 mg/kg Bevacizumab intraperitoneally; controls received saline. Tumour IFP was measured in sedated mice (Hypnorm) on days 1, 3 and 5 post injection, using the wick-in-needle technique. Experiments were conducted under Home Office licence and approved by the local ethical committee. Results: Groups of 8 treated and control tumours were examined on days 1, 3 and 5 (n = 48). IFP was significantly lower (p<0.0001) on day 5 in treated than control tumours (mean ± SD 15.1 ± 4.7 cf 36.9 ± 5.6 mm Hg). No significant differences (p>0.05) between treated and control groups were seen on day 1 (31.8 ± 3.5 cf 30.6 ± 3.1 mm Hg) or day 3 (33.4 ± 5.5 cf 31.5 ± 3.2 mm Hg). No data were acquired on day 7 as the tumours ulcerated. Conclusions: Our data show that Bevacizumab causes a significant reduction of tumour IFP, but not until 5 days after treatment. Reduced IFP could augment uptake of cytotoxic drugs into tumour cells, hence timing of Bevacizumab relative to the first dose of chemotherapy could be of critical importance. No significant financial relationships to disclose.