Abstract
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.
Highlights
Surgical excision and ionizing radiation of affected sites have been the mainstay for treatment of cancer patients for decades
To investigate if EBC-46 activated protein kinase C (PKC), we initially examined the production of reactive oxygen species following treatment of PMN
We show that intra-lesional treatment with EBC-46, a novel PKC-activating compound with apparent specificity for PKC-b isoforms, induces permeability of endothelial cell monolayers in vitro, as well as vascular swelling and apparent disruption of vessel morphology in vivo
Summary
Surgical excision and ionizing radiation of affected sites have been the mainstay for treatment of cancer patients for decades. Efficacy of these treatments can be limited by various factors including the condition of the patient, the proximity of adjacent vital tissues, inaccessibility of the tumor and intolerance of normal tissue for repeated courses of treatment. In some of these cases, intra-tumoral treatment may be more appropriate, when surgical intervention is not possible. Intra-tumoral treatment may have the advantage of allowing for much higher drug concentrations at the tumor site, and potentially less toxicity than systemic agents. A limiting factor for greater use of intra-tumoral treatments appears to be lack of suitable agents rather than delivery technologies
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