Abstract 3936: A hemoglobin-based oxygen carrier enhances chemotherapy in a rat orthotopic HCC model

Abstract

Abstract Background and aims: Chemotherapy, as a regular treatment for non-resectable and recurrent hepatocellular carcinoma (HCC), its efficiency is largely limited by the high incidence of chemo-resistance. In the past several years, extensive evidence has demonstrated that tumor cells are exposed to diverse levels of hypoxia (oxygen deficiency) in vivo and this hypoxic stress acts as one of the major forces inducing chemo-resistance in tumors. Additionally, some recent studies reported that improving tumor oxygenation could enhance the therapeutic efficacy, thereby serving as a novel strategy for cancer management. In this study we aimed to examine whether a hemoglobin-based oxygen carrier could increase tumor oxygenation and thus enhance the efficiency of TACE in a rat orthotopic HCC model. Materials and methods: An orthotopic HCC model was established and TACE performed as reported previously. Real-time partial pressure of oxygen (pO2) inside tumor tissue was monitored with OxyLab pO2TM. Efficacy of O2 carrier in delivering O2 to tumor was tested by comparing pO2 measurements before or after systemic delivery of the carrier. Sensitization of chemotherapy (cisplatin) in TACE by O2 carrier was examined with 4 different therapeutic regimens, which included cisplatin (1mg/kg) + O2 carrier (0.2g/kg), cisplatin (1mg/kg) + O2 carrier (0.4g/kg), cisplatin (3mg/kg) + O2 carrier (0.2g /kg), cisplatin (3mg /kg) + O2 carrier (0.4g/kg). In each regimen, a separate group of rats receiving mock buffer instead of O2 carrier was set as control. For all the therapeutic regimens, single administration of O2 carrier or mock buffer via tail vein was performed 1 hr before TACE. Tumor response was evaluated at macroscopic and microscopic levels at day 21 after therapy. Results: Both significant augmentation in pO2 readings inside tumor tissues and a right-shift of pO2 frequency distribution were observed after O2 carrier administration (0.4g/kg). Tumor growth was most strikingly inhibited in rats treated with regimen combining 3mg/kg of cisplatin and 0.4g/kg of O2 carrier. Alteration of average estimated tumor volume in this regimen was 570 mm3 (pre-trx) vs 410 mm3 (post-trx) in O2 carrier -treated rats in contrast to 620 mm3 (pre-trx) vs 1980 mm3 (post-trx) in comparable control rats (p<0.05). Microscopic examination revealed that complete or nearly complete necrosis occurred more frequently in rats received this regimen (21%) compared with all the other regimens (0∼10%). Conclusion: Hypoxic levels inside tumor tissue could be alleviated by systemic delivery of a hemoglobin-based oxygen carrier in the rat orthotopic HCC model. Pre-administration of a certain amount of O2 carrier (0.4g/kg) could greatly improve the therapeutic efficacy of cisplatin (3mg/kg) in TACE. Whether delivery of O2 carrier in other ways (multiple dosages or continuous perfusion) is more efficient in sensitizing cisplatin is worth further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3936. doi:1538-7445.AM2012-3936