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Genetic Engineering of Clostridial Strains for Cancer Therapy
Published in Ananda M. Chakrabarty, Arsénio M. Fialho, Microbial Infections and Cancer Therapy, 2019
Maria Zygouropoulou, Aleksandra Kubiak, Adam V. Patterson, Nigel P. Minton
Improvement of the colonization efficiency and elimination of the outer rim have been the focus of ongoing efforts in the development of clostridial cancer therapy. The administration of clostridial spores has been combined with conventional therapies and various strategies aiming to amplify the hypoxic conditions in the tumor. The expectation was that with the complementation and synergy of different approaches not only would the hypoxic core be lysed but also the viable outer rim ablated. On a preclinical level, clostridial spores have been combined with radiation [27, 28], cytotoxic chemotherapeutic drugs [5, 22] (e.g., mitomycin C, vinorelbine, and docetaxel), vascular targeting agents (dolastatin D-10 [5], combretastatin A-4 [12], and vadimezan [19]), as well as reduction of the oxygen levels in the respired air of animals [29] or induction of tumor hyperthermia [30].
The oxygen effect and therapeutic approaches to tumour hypoxia
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Michael R. Horsman, J. Martin Brown, Albert J. van der Kogel, Bradly G. Wouters, Jens Overgaard
The inadequate vascular supply to tumours is one of the major factors responsible for the development of hypoxia. The tumour vasculature develops from normal tissue vessels by the process of angiogenesis. This is an essential aspect of tumour growth, but this tumour neo-vasculature is primitive and chaotic in nature and is often unable to meet the oxygen demands of rapidly expanding tumour regions, thus causing hypoxia to develop. The importance of the tumour neo-vasculature in determining growth and the environmental conditions within a tumour therefore makes it an attractive target for therapy (20). The first and most popular is the use of drugs to prevent angiogenesis from occurring (angiogenesis inhibitors [AIs]), while the second involves the use of therapies that can specifically damage an already established vasculature (vascular disrupting agents [VDAs]). Examples of AIs clinically tested include inhibitors of vascular endothelial growth factor such as bevacizumab; tyrosine kinase inhibitors including sorafenib (Bay 43-9006/nexavar), sunitinib (SU11248/sutent), vanatanib (PTK787/ZX 222584) and vandetanib (ZD6474/zactima); and thalidomide and related analogues (lenalidomide, pomalidomide). Clinically relevant VDAs include tubulin binding agents like combretastatin A-1 phosphate, OXi4503, ombrabulin (AVE8062) and plinabulin (NPI-2358); the flavonoid compound vadimezan (ASA404); and chemotherapeutic drugs such as the vinca alkaloids and arsenic trioxides.
Platelets for advanced drug delivery in cancer
Published in Expert Opinion on Drug Delivery, 2023
Daniel Cacic, Tor Hervig, Håkon Reikvam
The inflammatory anticancer effect of anti-PD-1-conjugated platelets was also potentiated by incorporating them into a hydrogel loaded with the tyrosine kinase inhibitor pexidartinib [153]. This incorporation depleted the resection sites of tumor-associated macrophages in tumor-bearing mice with different cancer types by blocking CSF1R signaling. Furthermore, concomitant treatment with vadimezan increases the recruitment of anti-PD-1-conjugated platelets through tumor vascular disruption, resulting in substantially improved survival in several murine cancer models [154]. Lastly, PTT has been combined with anti-PD-1-conjugated platelets to enhance the immune stimulatory effect through ‘wounding’ of the tumor to increase platelet infiltration and tumor antigen release [155,156].