pep005 and Neoplasms

Ingenol mebutat (IM)-gel is effective for the topical treatment of epithelial tumors, including actinic keratoses (AKs) or anogenital warts (AGW). AK patients treated with IM develop intensified inflammatory reactions on sights of prior clinical visible or palpable AKs as compared to the surrounding actinically damaged skin, suggesting the induction of a tumor cell-directed inflammation. AGW patients treated with IM develop even stronger inflammatory reactions with large erosions, suggesting a directed inflammatory response against HPV-infected keratinocytes. Of note, even widespread erosions heal very fast without any superinfections. Here, we set out to elucidate underlying molecular and cellular mechanisms of these clinical observations.. The effects of IM (10. Ingenol mebutat significantly and dose-dependently induced the expression of proinflammatory chemokines (CXCL8, CCL2) and AMP (RNase7, HBD3) in HEK and epithelial cancer cell lines. A significantly stronger induction of CXCL8 and CCL2 was observed in our tested tumor cells as compared to HEK. We did not observe any significant effect of IM on HEK migration, respectively wound healing responses in vitro for any tested concentration (10. Our data suggest that tumor cells are more susceptible to IM as compared to differentiated HEK. This is evident by a stronger IM-mediated induction of proinflammatory chemokines in tumor cells, which may result in a tumor cell-directed inflammatory response and rapid tumor destruction. In addition, IM induces AMP in keratinocytes and seems not to severely interfere with keratinocyte migration, which contributes to a fast and uncomplicated wound healing. Surprising is a selective inhibition of keratinocyte migration by IM at the concentration of 10

Topics: Administration, Topical; Antimicrobial Cationic Peptides; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemokines; Condylomata Acuminata; Diterpenes; Gene Expression Regulation; HEK293 Cells; Humans; Inflammation; Keratinocytes; Keratosis, Actinic; Neoplasms; Papillomaviridae; Wound Healing

Ingenol-3-angelate is a new local chemotherapeutic agent in clinical trails that induces primary necrosis of tumour cells and transient local inflammation. Here we show that cure of subcutaneous tumours with ingenol-3-angelate (PEP005) resulted in the generation of anti-cancer CD8 T cells that could regress metastases. Furthermore, PEP005-mediated cure synergized with several CD8 T cell-based immunotherapies to regress further distant metastases. PEP005 was shown to have adjuvant properties, being able to upregulate CD80 and CD86 expression on dendritic cells in vivo, and to promote CD8 T cell induction when co-delivered with a protein antigen. PEP005 thus emerges as a unique local chemotherapeutic immunostimulatory debulking agent that could be used in conjunction with immunotherapies to promote regression of metastases.

Topics: Adjuvants, Immunologic; Animals; Cancer Vaccines; Carcinoma, Lewis Lung; Cell Culture Techniques; Chickens; Colonic Neoplasms; Dendritic Cells; Diterpenes; Female; Humans; Immunization; Lung Neoplasms; Melanoma, Experimental; Mice; Neoplasm Transplantation; Neoplasms; T-Lymphocytes

The sap of Euphorbia peplus, commonly know as 'petty spurge', 'radium weed' or 'milkweed' has been used for centuries as a traditional treatment for skin conditions, including warts, corns and cancers of the skin. Documentation of its use by medical professionals to treat basal cell carcinoma (BCC) dates from the early 19 century. Individuals who participated in a 1988 survey of home treatments for cancer indicated the sap of E. peplus was an effective cure for actinic lesions leading the investigators to suggest that this potential utility should be further explored in controlled clinical trials. The fractionation of the sap E. peplus using solvents of varying polarity yielded several macrocyclic diterpenes, many of which were found to have cytotoxic activity or the ability to influence cellular differentiation. Ultimately, ingenol 3-angelate (I3A) of PEP005, emerged as a promising potential new anti-cancer treatment. Here we report the proceedings from the First International Conference on PEP005, covering the exciting potential of PEP005 as the therapeutic agent for the treatment of skin cancer, leukemia and bladder cancer.

Topics: Administration, Topical; Animals; Antineoplastic Agents, Phytogenic; Diterpenes; Esters; Humans; Leukemia; Melanoma; Mice; Neoplasms; Skin Neoplasms; Urinary Bladder Neoplasms