Hepatic arterial infusion of bevacizumab in combination with oxaliplatin reduces tumor growth in a rat model of colorectal liver metastases

Abstract

Unresectable colorectal liver metastases are commonly treated with systemic chemotherapy (SCT). Clinical studies on the effect of additional systemic application of bevacizumab (BE), a monoclonal antibody directed against vascular endothelial growth factor, to SCT showed a slight increase of patient survival. Herein, we studied in a rat model of colorectal liver metastasis whether a locoregional application of oxaliplatin (OX) and BE via hepatic arterial infusion (HAI) is more effective to inhibit metastatic growth compared to systemic drug application. Ten days after implantation of CC531 colorectal cancer cells into the left liver lobe of WAG/Rij rats, animals underwent either HAI or systemic intravenous application of BE (5 mg/kg body weight), OX (85 mg/m(2) body surface) or a combination of both. Sham-treated animals received saline and served as controls. Tumor volume was measured at days 10 and 13 using three dimensional ultrasound. At day 13 tumor tissue was analyzed histologically and immunohistochemically. Systemic application of OX, BE or their combination did not affect tumor volume when compared to controls. In contrast, HAI of BE and particularly the combination of BE and OX significantly reduced tumor volume. In the tumor tissue this was associated with a decrease of vascularization and cell proliferation as well as an increase of cell apoptosis, as indicated by a decreased number of PECAM-1- and PCNA-positive cells and an increased number of cleaved caspase-3-positive cells. Locoregional administration of BE, particularly in combination with OX, enhances the inhibitory effect on hepatic metastatic growth compared to systemic application of the drugs.

Mechanical ventilation drives pneumococcal pneumonia into lung injury and sepsis in mice: protection by adrenomedullin

“…For analysis of apoptosis, staining against cleaved caspase-3 (CC3) was used as an indicator of apoptotic cell death as described previously [20]. In brief, paraffin sections were incubated overnight with a polyclonal anti-cleaved caspase-3 antibody (Asp175, 1:50; Cell Signaling Technology, Frankfurt, Germany).…”

Liver-directed chemotherapy of cetuximab and bevacizumab in combination with oxaliplatin is more effective to inhibit tumor growth of CC531 colorectal rat liver metastases than systemic chemotherapy

“…After HAI the catheter was removed and the gastroduodenal artery was ligated. For sCHT the subhepatic vena cava was punctured with a 23G needle (Troge Medical GmbH, Hamburg, Germany) according to previously published standards [5]. …”

“…It is well known that liver-directed chemotherapy, which is achieved by hepatic arterial infusion, yields reproducibly higher response rates compared to sCHT both in preclinical and clinical settings [2, 5]. However, the overall value of HAI remains unclear [6].…”

Hepatic arterial infusion plus systemic chemotherapy as third-line or later treatment in colorectal liver metastases

“…The liver is the most common site of involvement for patients with CRC. Approximately 50 % of CRC patients will eventually develop liver metastases during the course of the disease [2]. These colorectal liver metastases (CLMs) are usually an indicator of poor prognosis.…”