Browsing by Subject "melanoma"
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(2021)Background and objectives: Cancer is one of the leading causes of death worldwide, and resistance to current treatments demands the continuous development of novel cancer therapies. Cancer immunotherapy aims to induce anticancer immune responses that selectively target cancer cells. Viruses can also be harnessed to elicit tumor-specific immune responses and to improve the response rates of other concomitant cancer therapies. The purpose of this study was to develop a novel viral vector-based cancer vaccine for intratumoral immunotherapy. By using the previously developed PeptiENV cancer vaccine platform, the vector viruses were coated with cell-penetrating peptide (CPP) sequence-containing tumor peptides in an attempt to further drive the immune responses elicited by the vector against cancer cells. The efficacy of the PeptiENV complex as a cancer vaccine was assessed by following its effects on tumor growth and the development of local and systemic antitumor immune responses. Methods: The PeptiENV complex formation was assessed by a surface plasmon resonance (SPR) analysis. Dendritic cell (DC) activation and antigen cross-presentation were studied using the murine JAWS II dendritic cell line. The development of cellular immune responses against tumor antigens was first studied by immunizing mice with the PeptiENV complex. The antitumor efficacy and immunity of intratumoral PeptiENV administration were then studied using the murine melanoma models B16.OVA and B16.F10.9/K1. In addition to intratumoral PeptiENV treatment, some of the B16.F10.9/K1-implanted mice were also treated with an anti-PD-1 immune checkpoint inhibitor (ICI) to study the PeptiENV complex as a biological adjuvant for ICIs. Results: The SPR analysis confirmed that CPP-containing peptides can be stably anchored onto the viral envelope of the viral vector. The in vitro results showed that the PeptiENV complex does not hamper the presentation of antigens at the surface of DCs. Additionally, the viral vector was found to activate DCs seen as a change in the cells’ morphology and surface protein expression. Immunizing mice with the PeptiENV complex induced a robust antigen-specific cytotoxic T cell response. Upon intratumoral administration in vivo, the PeptiENV cancer vaccine was not capable of inducing tumor growth control against B16.OVA melanoma, although it did still elicit robust systemic and local antitumor T cell responses. In the treatment of B16.F10.9/K1 melanoma, however, the PeptiENV complex induced efficient tumor growth control, which resulted in a significant survival benefit. Additionally, co-administration of anti-PD-1 resulted in an additive therapeutic effect. Discussion and conclusions: The present study describes a novel, highly immunogenic viral vector-based cancer vaccine that has the potential to be used as an adjuvant treatment for ICI therapy. Subsequent studies could be conducted to gain a deeper understanding of the immunological mechanisms underlying the antitumor efficacy of the cancer vaccine complex. Moreover, this novel PeptiENV complex could also be further developed as an infectious disease vaccine platform against emerging pandemics. However, the effects of pre-existing antiviral immunity on the efficacy of the cancer vaccine should be explored in future studies.
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(2018)Marine organisms can be regarded as a diverse source of bioactive compounds with the possibility to discover novel drug lead molecules. Sea sponges produce bromine containing alkaloids, bromotyrosines, from which several are active against cancer. Some bromotyrosines have spirocyclic structure and the innate three-dimensionality and structural novelty of spirocycles make them an interesting option in drug design. Clavatadine C, extracted from sponge Suberea clavata, is a bromine containing spirocyclohexa-dienylisoxazoline alkaloid. It’s symmetric spirocyclic core can be viewed as a restricted derivative of open chain oximes, such as purpurealidin I, a bromotyrosine extracted from Pseudoceratina purpurea. Earlier work with purpurealidin I derivatives against melanoma cell line has had some promising results. Inspired by these earlier results, eight spirocyclic clavatadine C derivatives were synthesized according the published synthesis route. The activities of seven synthesized clavatadine C derivatives were tested on A375 melanoma cell line. All spiro derivatives were active with CC50 values ranging between 1.0 μM and 3.4 μM. Also, the activities of 10 earlier synthesized bromotyrosine derivatives were tested, from which four open chain oximes had CC50 values between 13.5 μM and 27.8 μM. Interestingly, the most active compounds were chlorinated and unhalogenated spirocyclic derivatives. In general, the spirocyclic compounds were 2- to 8-fold more active than the corresponding open chain oximes. The selectivity of active compounds was determined as cytotoxicity against Hs27 fibroblasts and by comparing the CC50 values of these two cell lines. The most selective compound was brominated derivative which had three times better selectivity against melanoma cells. The weak selectivity was consistent with the trend with open chain oxime analogs. Despite the selectivity issue, the improved activity of spirocyclic derivatives are promising and support for further investigation of marine-based spirocyclic bromotyrosine derivatives against melanoma.
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(2017)Melanoma is the most severe case of skin cancer and there is no curative treatment if it has progressed. Despite the recent advances in drug therapy tens of thousands of patients die of melanoma annually. There is still need for new antimelanoma drugs for which marine compounds are a potential source. Halogens are common elements in drug molecules as they enhance their molecular properties. So far most of the halogenated drugs contain fluorine and/or chlorine but the role of bromine and iodine is probably growing in the future due to halogen bonding. Bromotyrosines are originally isolated from Verongiida-order sponges but whether they are truly of bacterial origin is under controversy. All bromotyrosine compounds consist of brominated tyrosine and/or tyramine residues or their derivatives. Purpurealidin I is one of the newest bromotyrosine derivatives extracted from Pseudoceratina purpurea and it has shown activity against melanoma. In this study eight new purpurealidin I derivatives were synthesized following a successful route previously designed. All synthesized derivatives contained the original N-oxime structure which's stereochemistry was determined to be E by X-ray crystallography. Cytotoxicity against A375 melanoma cells was determined for seven compounds synthesized here and for 15 compounds synthesized previously. All seven compounds and one previously synthesized purpurealidin I analog were active with CC50 values between 4,7 and 22,1 µM. The previously synthesized bromotyrosine derivative intermediates and aerophobin-1 analogs were not active. The selectivity of the active compounds was calculated by determining their CC50 value against Hs27 fibroblast cells. None of the compounds showed remarkable selectivity the most selective 2-pyridin containing derivative having four times better selectivity against melanoma. The tyrosine part and N-oxime seem to be important parts to preserve while the tyramine part can be modified more freely and maintain the activity. Still more derivatives need to be synthesized and tested to confirm these observations. More data is also needed considering the selectivity of the compounds.
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