新型PKC激活劑EBC-46的病灶內注射迅速消除小鼠模型中的腫瘤。

Intra-Lesional Injection of the Novel PKC Activator EBC-46 Rapidly Ablates Tumors in Mouse Models

 

 

October 2014 · PLoS ONE 9(10):e108887DOI: 10.1371/journal.pone.0108887

Source

 · PubMed

Authors:

Glen M Boyle at Queensland Institute of Medical Research

42.2

 · Queensland Institute of Medical Research

 

病灶內化療用於治療皮膚惡性腫瘤已經使用了數十年,與全身性藥物相比,它允許更高的局部藥物濃度和更低的毒性。在這裡,我們描述了一種新型的二萜酯EBC-46,並提供臨床前數據支持其作為病灶內治療的用途。在一系列同基因和異種移植模型中,單次注射EBC-46會引起快速炎症和血液大量流入,隨後是傷口形成和腫瘤快速消融 EBC-46誘導了純化的人多形核細胞的氧化爆發,這被蛋白激酶C抑製劑bisindolylmaleimide-1阻止。與結構相關的佛波醇12-肉荳蔻酸酯13-乙酸酯(PMA)相比,EBC-46激活了更特異性的PKC亞型(PKC-βI-βII-α和-γ)。儘管EBC-46在體外抑制細胞生長的功效比PMA低三倍,但它在體內治愈腫瘤方面更為有效。通過離體培養物注射後四小時,沒有明顯的存活腫瘤細胞。來自治療小鼠的藥代動力學曲線表明,與注射到正常皮膚相比,病灶內注射後EBC-46優先保留在腫瘤內,並導致明顯更大的局部反應(紅斑,水腫)。與bisindolylmaleimide-1一起注射會降低EBC-46的功效。治療後血管完整性的喪失通過體外內皮細胞單層滲透性的提高和體內治療腫瘤的CD31免疫染色來證明。我們的結果表明,在癌前臨床模型中,病灶內單次注射EBC-46會導致PKC依賴性出血性壞死,腫瘤細胞快速死亡和實體瘤的完全的治愈。

 

Abstract and Figures

Intra-lesional chemotherapy for treatment of cutaneous malignancies has been used for many decades, allowing higher local drug concentrations and less toxicity than systemic agents. Here we describe a novel diterpene ester, EBC-46, and provide preclinical data supporting its use as an intra-lesional treatment. A single injection of EBC-46 caused rapid inflammation and influx of blood, followed by eschar formation and rapid tumor ablation in a range of syngeneic and xenograft models. EBC-46 induced oxidative burst from purified human polymorphonuclear cells, which was prevented by the Protein Kinase C inhibitor bisindolylmaleimide-1. EBC-46 activated a more specific subset of PKC isoforms (PKC-βI, -βII, -α and -γ) compared to the structurally related phorbol 12-myristate 13-acetate (PMA). Although EBC-46 showed threefold less potency for inhibiting cell growth than PMA in vitro, it was more effective for cure of tumors in vivo. No viable tumor cells were evident four hours after injection by ex vivo culture. Pharmacokinetic profiles from treated mice indicated that EBC-46 was retained preferentially within the tumor, and resulted in significantly greater local responses (erythema, oedema) following intra-lesional injection compared with injection into normal skin. The efficacy of EBC-46 was reduced by co-injection with bisindolylmaleimide-1. Loss of vascular integrity following treatment was demonstrated by an increased permeability of endothelial cell monolayers in vitro and by CD31 immunostaining of treated tumors in vivo. Our results demonstrate that a single intra-lesional injection of EBC-46 causes PKC-dependent hemorrhagic necrosis, rapid tumor cell death and ultimate cure of solid tumors in pre-clinical models of cancer.

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