Drug-eluting Beads for TACE

Currently, there is intense research activity in the area of nanotechnology and drug-delivery systems. The ideal drug-loaded carriers should deliver the agent precisely, release it in a controlled and sustained manner and achieve high intra-tumour drug concentration for a sufficient period, without damaging the surrounding hepatic parenchyma.

3-BromopyruvateIntra-arterial Injection for Liver Cancer-preclinical Studies

3-Bromopyruvate (3-BrPa) is an example of a drug disrupting a metabolic pathway, which has been recently tested via transcatheter infusion. 3- BrPa is a potent ATP inhibitor of glycolysis. In a recent study, conducted on human hepatoma cell lines, 3-BrPa induced HCC cell apoptosis, besides inhibiting ATP production. This apoptotic cell type of death was likely responsible for the full effect of 3-BrPa on growth suppression, as induced apoptosis reached over 90% within six hours of treatment. It should be noted that previous studies have suggested that apoptosis is an ATPdependent process.

In another study, cell death induced by 3-BrPA was shown to contain both apoptotic and necrotic components, in a ratio depending on the 3-BrPA concentration. This study also demonstrated that 3- BrPA preferentially kills cancer cells with mitochondrial defects and tumour cells in a hypoxic environment. Preliminary studies on the rabbit Vx-2 liver tumour model with direct intraarterial infusion of 3-BrPa showed complete tumour destruction, without affecting the surrounding normal liver parenchyma. In a more recent VX2 animal study, one-hour intra-arterial injection of 1.75mM of 3-BrPa resulted in tumour cell death in all treated animals. Moreover, the one-hour intra-arterial infusion of 3-BrPA resulted in complete tumour destruction and was significantly greater than that of serial bolus injection. In addition, animals treated in this manner had no liver toxicity. Nevertheless, the exact mechanisms of resistance of normal cells against 3-BrPa, as well as the exact pathway of 3-BrPa action, are still under investigation.

Advanced Imaging Techniques for Monitoring the Efficacy of TACE
Despite the fact that evaluating the effectiveness of TACE is critical in determining the success of treatment and would help to guide subsequent therapeutic planning, there is no single reliable imaging method for monitoring the early response to this treatment method. Good iodised oil retention at CT is associated with substantial prolongation of median survival of the patient, but does not indicate complete tumour necrosis, nor is it correlated with the size or extent of the necrotic area. On dynamic CT studies, hyper-attenuating iodised oil impairs assessment of residual tumour enhancement. Enhancing areas in the embolisation site on gadolinium-enhanced MR images presumably represent viable tumour but could also result from post-treatment granulation tissue.

Perfusion-diffusion MRI can successfully overcome this obstacle, as lipiodol does not obscure gadolinium enhancement and measurement of increased free water content within the tumour translates into cancerous cell death. Furthermore, diffusion MRI may prove more useful in the early post-treatment period after TACE, when tumours are not expected to change in size, despite the fact that they may be nonviable. A recent study by the authors’ group showed that diffusion-weighted images and the generated apparent diffusion coefficient (ADC) maps provide functional information on a molecular level regarding the viability of tumour cells after TACE, allowing, therefore, an cellular-based assessment of treatment response after TACE. Viable tumour cells have intact cellular membrane, which restrict the movement of water molecules, resulting in low ADC values. With cellular death, cellular membranes eventually are disrupted, and diffusion of water molecules is no longer restricted, leading to an increase of the ADC values within the necrotic tumour tissue, confirming, therefore, the presence and invasion of extracellular water inside the cancerous cells. In this study, there was a statistically significant decrease in the ADC value of treated HCC after TACE, compared to values before treatment (p=0.026). In this way, the ADC value measurements allow for the accurate quantification of the degree of cellular damage, and this may prove especially valuable after TACE because of the wide spectrum of histopathologic findings, ranging between complete necrosis and the absence of necrosis.

Conclusion

Knowledge of the molecular basis of hepatic tumourigenesis is evolving continuously. Main areas of interest include the development of new cytostatic agents that interact upon some disrupted pathways, inhibit angiogenesis and limit chemotherapeutic dose-related toxicity. Phase I/II/III studies are currently testing whether antiangiogenesis agents, inhibitors of growth-factorsignalling and cell cycle enzymes, non-specific growth inhibitory agents, specific antagonists of HCC tumour markers and anti-inflammatory agents may have a potential impact on the treatment of liver cancer. The combination of these emerging agents with TACE seems challenging and promising. Moreover, monitoring the efficacy of TACE by imaging is also crucial for effective patient care and prolongation of patient survival.