Hypoxia-activated cytotoxic agent tirapazamine enhances hepatic artery ligation-induced killing of liver tumor in HBx transgenic mice

Abstract

Transarterial chemoembolization (TACE) is the main treatment for intermediate stage hepatocellular carcinoma (HCC) with Barcelona Clinic Liver Cancer classification because of its exclusive arterial blood supply. Although TACE achieves substantial necrosis of the tumor, complete tumor necrosis is uncommon, and the residual tumor generally rapidly recurs. We combined tirapazamine (TPZ), a hypoxia-activated cytotoxic agent, with hepatic artery ligation (HAL), which recapitulates transarterial embolization in mouse models, to enhance the efficacy of TACE. The effectiveness of this combination treatment was examined in HCC that spontaneously developed in hepatitis B virus X protein (HBx) transgenic mice. We proved that the tumor blood flow in this model was exclusively supplied by the hepatic artery, in contrast to conventional orthotopic HCC xenografts that receive both arterial and venous blood supplies. At levels below the threshold oxygen levels created by HAL, TPZ was activated and killed the hypoxic cells, but spared the normoxic cells. This combination treatment clearly limited the toxicity of TPZ to HCC, which caused the rapid and near-complete necrosis of HCC. In conclusion, the combination of TPZ and HAL showed a synergistic tumor killing activity that was specific for HCC in HBx transgenic mice. This preclinical study forms the basis for the ongoing clinical program for the TPZ-TACE regimen in HCC treatment.hypoxia | hepatocellular carcinoma | orthotopic | transarterial embolization H epatocellular carcinoma (HCC), the sixth most common solid malignancy, accounts for approximately three-quarters of a million deaths worldwide every year (1). Over the past two decades, the incidence of HCC has remained high in Asia and has steadily increased in the United States and Europe (1). Treatment for HCC largely depends on the stage of the disease. Diagnosis is usually delayed, as ∼30-40% of the patients are already in the intermediate stage at their initial visit, and transarterial chemoembolization (TACE) is the most commonly used treatment for these patients (2). However, TACE achieves only a 20-30% tumor remission rate, and recurrence is common, resulting in a 3-y survival rate of only ∼30% (3). This poor survival rate needs to be improved.The mechanism by which arterial embolization preferentially kills HCC but spares adjacent liver tissues arises from the unique dual blood supply to the liver. Normal liver receives 75% of its blood supply from the portal vein (PV) and the remaining 25% from the hepatic artery (HA) (4). In contrast, HCC almost exclusively receives its blood supply from the HA (5). Based on this unique pattern, embolization has been used to selectively block the arterial blood supply to HCC, causing transient but profound ischemia and depriving HCC cells from essential oxygen and nutrients, thus killing the tumors.However, because of the heterogeneity of the tumor vessels within HCC, the embolization of the tumor-feeding arteries usually results in different degrees of ischemia and hypoxia, rang...

Hypoxia inducible factors in hepatocellular carcinoma

“…OXY111A is currently under phase 1 and 2 clinical trials in patients with malignancies of the liver, pancreas and biliary tract. Moreover, hypoxia can be harnessed to selectively activate cytotoxic pro-drugs such as tirapazamine (TPZ) and TH-302 [ 125 , 126 ]. By using a HBx-transgenic murine model, TPZ co-operated with arterial embolization to induce tumor necrosis without affecting normal liver cells [ 125 ].…”

Preparation of microspheres encapsulating sorafenib and catalase and their application in rabbit VX2 liver tumor

“…Another limitation of the current clinical TACE therapy is that the commonly used lipiodol embolization of hepatic arteries is usually not durable. Chemotherapeutic drugs in lipiodol are released rapidly, and the blood flow of liver tumors is restored quickly [29]. This observation is supported by the finding that angiography at the second or subsequent embolization usually indicates the recanalization of the hepatic artery.…”

Theranostics in Interventional Oncology: Versatile Carriers for Diagnosis and Targeted Image-Guided Minimally Invasive Procedures

“…This therapeutic strategy is actually under investigation and should be made available shortly for cancer patients (Bize et al, 2016; Duran et al, 2018). Similarly, targeting tumor hypoxia using hypoxia-activated prodrugs originally developed for systemic delivery were tested in locoregional delivery or in combination therapy (TACE + intravenous hypoxia-activated prodrug) in preclinical models for liver cancer and held promise in achieving meaningful results once translated in the clinic (Lin et al, 2016; Duran et al, 2017). The use of theranostic nanoparticules offers a myriad of possibilities in the setting of TACE where superselective disease targeting and high drug dose delivery can overcome challenges faced by systemic delivery such as biodistribution, tumor uptake and toxicity.…”