Therapeutic effects of artesunate in hepatocellular carcinoma: repurposing an ancient antimalarial agent.

OBJECTIVES: Artemisinins are antimalarial drugs that exert potent anticancer activity. We evaluated the effects of artesunate, a semisynthetic derivative of artemisinin, on tumor growth, angiogenesis, the unfolded protein response, and chemoresistance in hepatocellular carcinoma. MATERIALS AND METHODS: The effect of artesunate was examined in HepG2 and BWTG3 cells under normoxic and hypoxic conditions and in a diethylnitrosamine-induced mouse model. Histology was performed with hematoxylin/eosin and reticulin staining. The expression of chemoresistance-related transporters and angiogenic and unfolded protein response factors was determined. Cytotoxicity was assessed by alanine and aspartate transaminase, lactate dehydrogenase, water-soluble tetrazolium salt, and caspase-3 activity assays. Small animal imaging was performed using dynamic contrast-enhanced MRI and choline PET to assess tumor progression. RESULTS: Artesunate dose dependently reduced cell viability (from 50 µmol/l; P<0.05) and increased caspase-3 activity (P<0.05) in HepG2 and BWTG3 cells. These effects were enhanced by hypoxia (from 12.5 µmol/l; P<0.01). Moreover, artesunate downregulated vascular endothelial growth factor and placental growth factor expression in vitro (both P<0.05) and in vivo (both P<0.01). In mice, artesunate decreased vessel density and tumor burden (both P<0.05). These in-vivo effects were enhanced by combination with sorafenib (P<0.05 and P=0.07, respectively), without apparent hepatotoxicity. Furthermore, artesunate modulated the unfolded protein response in vitro and in vivo, increasing proapoptotic signaling, and did not induce doxorubicin chemoresistance. CONCLUSION: These findings indicate that artesunate could offer a new approach to the therapy of hepatocellular carcinoma. Clinical trials with artesunate as monotherapy or in combination with current hypoxia-inducing approaches are necessary.

(188)Re-HDD/lipiodol therapy for hepatocellular carcinoma: an activity escalation study.

PURPOSE: The aim of this study was to investigate the feasibility of administering increasing activities of (188)Re-4-hexadecyl-1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol/lipiodol ((188)Re-HDD/lipiodol) for the treatment of hepatocellular carcinoma (HCC) in patients with well-compensated cirrhosis. METHODS: The activity levels were increased by 1.1 GBq/step after a 6-week interval without unacceptable adverse events in at least five consecutive patients. Absorbed doses to the various organs were calculated according to the MIRD formalism, based on three gamma-scintigraphic studies. Response was assessed by means of MRI and alpha-fetoprotein (AFP) monitoring. RESULTS: Thirty-five treatments were carried out in 28 patients. Activities from 4.8 to 7.0 GBq (188)Re-HDD/lipiodol were administered via a transfemoral catheter. The mean absorbed dose to the liver (including tumour) was 7.6+/-2.2, 9.8+/-4.9 and 15.2+/-4.9 Gy for the 4.8-, 5.9- and 7.0-GBq groups, respectively. Treatment was well tolerated at all activity levels. Further escalation of the administered activity was not feasible owing to limitations related to the radiolabelling procedure. Response assessment on MRI showed partial response, stable disease and disease progression in 1, 28 and 2 assessable treatments, respectively. In 8 of 17 treatment sessions with an initially elevated AFP, a reduction ranging from 19% to 97% was observed 6 weeks later. CONCLUSION: Following the intra-arterial administration of 4.8-7.0 GBq (188)Re-HDD/lipiodol in patients with HCC and well-compensated liver cirrhosis, no severe adverse events occurred. Further escalation was not feasible owing to limitations in the radiolabelling procedure.

Radiolabeled lipiodol therapy for hepatocellular carcinoma in patients awaiting liver transplantation: pathology of the explant livers and clinical outcome.

BACKGROUND: Liver transplantation has become an important curative treatment option for hepatocellular carcinoma (HCC). Criteria for transplantation are strict and, therefore, it is crucial that patients awaiting transplantation do not suffer disease progression. One of the therapeutic options to achieve disease stabilization is neoadjuvant radiolabeled lipiodol treatment. This study aimed to document the dropout rate on the waiting list, the pathological findings on the explant livers, and the long-term outcome of patients treated with radionuclide therapy while awaiting transplantation. METHODS: Patients eligible for transplantation were treated with 2.1 GBq (131)I-lipiodol or 4.1 GBq (188)Re-HDD/lipiodol by transfemoral catheterization of the hepatic arteries. Tumor necrosis was assessed in the explant livers and follow-up data, such as dropout from the waiting list, recurrence, and survival following transplantation were retrospectively documented. RESULTS: In 5 of 22 explants, necrosis exceeded 90%. Two patients died while on the waiting list (10%) and 4 of 20 transplanted patients (20%) suffered recurrent disease. The overall recurrence-free survival was 19.7 months (range, 1.75-56), with a mean follow-up of 20.1 months. CONCLUSION: Our data support the evaluation on larger patient numbers to confirm the benefit of radiolabeled lipiodol in candidates for liver transplantation who are suffering from HCC.

188Re-HDD/lipiodol therapy for hepatocellular carcinoma: a phase I clinical trial.

UNLABELLED: The aim of this study was to investigate the pharmacokinetics, organ dosimetry, and toxicity after the intraarterial administration of (188)Re-labeled 4-hexadecyl-1,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol/lipiodol ((188)Re-HDD/lipiodol) for palliative treatment of hepatocellular carcinoma (HCC). A secondary objective was to document the response. METHODS: A mean activity of 3.60 GBq (188)Re-HDD/lipiodol (range, 1.86-4.14 GBq) was administered to 11 patients (16 treatment sessions) via a transfemoral catheter. The pharmacokinetic and dosimetric data were collected by means of venous blood samples, urine collections, and 4 or 5 gamma-scintigraphies over 76 h. Absorbed doses to the various organs were calculated according to the MIRD formalism, using the MIRDOSE3.1 software. The toxicity was assessed until 6 wk after administration by means of the Common Toxicity Criteria scale. The response was evaluated on MRI and by monitoring of the tumor marker. RESULTS: A fast blood clearance of the injected activity was observed with a calculated effective half-life of 7.6 +/- 2.2 h (+/-SD) in blood. The predominant elimination of the activity was through urinary excretion with a mean renal clearance of 44.1% +/- 11.7% (+/-SD) of the injected activity within the 76 h after administration. Fecal elimination was negligible. The calculated whole-body effective half-life was 14.3 +/- 0.9 h (+/-SD). The absorbed dose to the liver tissue, the lungs, the kidneys, and the thyroid was 4.5 +/- 1.9, 4.1 +/- 1.2, 0.9 +/- 0.7, and 0.3 +/- 0.1 Gy, respectively. Treatment was well tolerated, except in 2 patients. One Child B patient experienced a worsening of his liver dysfunction (hyperbilirubinemia) and another patient experienced dyspnea and coughing. Response assessment on MRI showed 1 case of partial response, disease stabilization in 11 treatments, and progressive disease in 1 treatment. In 5 of 8 treatment sessions with an initially elevated alpha-fetoprotein, a reduction (range, 19%-90%) was observed 6 wk later. CONCLUSION: After the intraarterial administration of 3.60 GBq (188)Re-HDD/lipiodol, a fast clearance of the activity appearing in the blood is observed and the predominant elimination is through urinary excretion. The tolerance as well as the preliminary response rates of the present phase I study are encouraging.