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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
TH-302 (evofosfamide), a 2-nitroimidazole hypoxia-activated prodrug of the DNA alkylator, bromo-isophosphoramide mustard, developed by Threshold Pharmaceuticals, has a mechanism of action similar to PR-104. After promising phase II data, two randomized phase III studies combining evofosfamide with gemcitabine in pancreatic cancer (MAESTRO), and with doxorubicin in soft tissue sarcoma (TH-CR-406/SARC021) were initiated. Disappointingly, both failed to meet their primary endpoints. The company will continue two phase II trials with another hypoxia-activated drug, tarloxotinib bromide, which releases an irreversible epidermal growth factor receptor tyrosine kinase inhibitor under severe hypoxia.
Clinical Aspects of Head and Neck Cancer
Published in Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke, Radiotherapy and Clinical Radiobiology of Head and Neck Cancer, 2018
Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke
The suboptimal results with tirapazamine in clinical studies were also due to the poor tumour penetration, given the fact that the drug is metabolised too fast in order to be optimally taken up by the hypoxic cell (Hicks 2004). Nevertheless, this limitation has been addressed in the second-generation of hypoxia-activated prodrugs. The tirapazamine analogue SN30000 has been designed with considerations of extravascular transport leading to more efficient tumour cell penetration and killing (Hicks 2010). Among the improved properties of SN30000 the following are to be mentioned: a threefold therapeutic gain as compared to tirapazamine on xenograft models and superior results when combined with fractionated radiotherapy (Hicks 2010). The preclinical test results of SN30000 warrant further research in HNC. Another prodrug, which has passed preclinical evaluation and currently is a phase III trial candidate in pancreatic cancer and soft tissue sarcoma is evofosfamide (TH-302) (Hunter 2015). While the novel hypoxia-activated drug is under investigation for several tumour sites, its value in HNC is yet to be demonstrated.
Hypoxia-activated prodrug derivatives of anti-cancer drugs: a patent review 2006 – 2021
Published in Expert Opinion on Therapeutic Patents, 2022
Emilie Anduran, Ludwig J Dubois, Philippe Lambin, Jean-Yves Winum
This review mainly focuses on related key patents from 2006 to 2021 of hypoxia-activated prodrug of anticancer agents. Tumor hypoxia poses a formidable challenge to therapeutic intervention. In recent years, several patent applications have been filed, showing that pharmaceutical companies and academic groups, essentially from China, were and are still very active in this field (Table 1). In the large number of HAP compounds described, the nitro (hetero)aromatic triggers are always considered as the best structural feature to achieve bioreductive properties. The majority of reported HAP compounds demonstrated better pharmacological properties compared to the parent anti-cancer compounds. Several in vitro and in vivo studies indicate hypoxia selectivity and therapeutic efficacy. To the best of our knowledge, except for the case of evofosfamide and tarloxotinib bromide, none of these HAP derivatives are currently in clinical trials, and it remains to be shown if these compounds are safe and effective. Companion diagnostics remain important for proper patient selection and to provide evidence of drug efficacy at early time points utilizing window-of-opportunity trials. In essence, the number of patent applications in the field of HAP emphasizes the hope that the exploitation of tumor hypoxia is still a promising area.
Managing the risk of toxicity in the treatment of elderly patients with soft tissue sarcomas
Published in Expert Opinion on Drug Safety, 2021
Samia Arifi, Anastasia Constantinidou, Robin L. Jones
The outcome and the safety of first-line anthracycline based chemotherapy in elderly patients with STS were investigated in a subgroup analysis of SARC021 trial [28]. This trial randomized patients to receive first line doxorubicin or doxorubicin plus evofosfamide. The primary analysis of this study showed no differences in OS or PFS between the two arms [29]. The older group aged ≥65 years old (n = 209) had a baseline PS of 0 or 1. Compared to the younger patients, there was no significant difference in both OS and PFS. However, adverse events (AEs) were significantly more common in older patients. Hematological toxicities (anemia, neutropenia and thrombocytopenia) occurred in 67% of patients vs 48% in the younger group. Sixty three percent of older patients experienced non-hematological AEs (fatigue, and diarrhea). There was no increase in cardiotoxicity in older patients (20% vs 35.8%, p = 0.06). Of note Dexrazoxane was administered to 22 and 12 patients in the younger and the older group respectively. Grade ≥3 AEs were significantly higher in older patients, especially, anemia and neutropenia. Older patients were more likely to discontinue therapy due to toxicity (30% vs 22%; p = 0.0001). Interestingly, quality of life analysis did not identify significant differences between younger and older group. PS 1 or 2 and age ≥ 65 were independently associated with greater hematological toxicities [28].
Hypoxic targeting and activating TH-302 loaded transcatheter arterial embolization microsphere
Published in Drug Delivery, 2020
Pengkai Ma, Jianhua Chen, Haixian Qu, Ye Li, Xiaohui Li, Xuemei Tang, Zhigang Song, Hainan Xin, Jinbang Zhang, Jingxue Nai, Zhiping Li, Zhijun Wang
TH-302 is a hypoxia-activated prodrug targeting the intra-tumoral hypoxic environment. The dinitroimidazole structure will be fragmented with an alkylating agent dibromoisophosphoramide mustard that selectively binds to the DNA and kills the tumor cells. Thus, it exerts little activity in the normoxic zone and fewer side effects on the normal tissues (Hu et al., 2010). It exhibited superior pre-clinical outcomes when used alone or combined with other chemotherapeutic drugs in several cells and xenograft models, such as non-small cell lung cancer, prostate cancer, melanoma, and pancreatic cancer, etc (Liu et al., 2012). Moreover, encouraging results have been obtained in clinical trials of evofosfamide (TH302) in the treatment of pancreatic cancer, soft tissue sarcoma, and heavily pretreated relapsed refractory multiple myeloma (Phillips, 2016). Therefore, delivering TH-302 to the hypoxia region through PLGA-based TACE MS might be worth exploring for HCC therapy.