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Alternative Tumor-Targeting Strategies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Tirapazamine (Figure 10.9) was the first hypoxia-activated prodrug to undergo clinical evaluation. The molecule contains two electrically neutral N-oxide moieties which become positively charged when reduced, a concept also used for the design of AQ4N (see below). However, it showed only modest clinical activity when used in combination with conventional chemotherapy. One explanation proposed for this disappointing result was that tirapazamine may have poor penetration into tumor blood vessels in hypoxic regions. Another potential explanation was based on the observation that, compared to their oxic counterparts, hypoxic cells are often quiescent (i.e., not replicating), and are thus less vulnerable to anti-proliferative agents such as DNA-damaging drugs and antimetabolites. Structure of tirapazamine (SR-4233).
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.
MELANOMA: SYSTEMIC THERAPY
Published in James Bishop, Cancer Facts, 1999
Radiotherapy is useful in palliating symptoms from local tumour effects, particularly in bone, subcutis, lymph nodes, mediastinum, and in spinal cord compression. Phase II studies have reported radiosensitising advantages of the use of concurrent procarbazine, cisplatin and fotemustine. Recommendations regarding the use of these and other radiosensitisers, such as tirapazamine, await evidence of efficacy in randomised studies. The management of specific metastatic problems in patients with disseminated melanoma is summarised in Table 42.2.
Iodinated cyanine dye-based nanosystem for synergistic phototherapy and hypoxia-activated bioreductive therapy
Published in Drug Delivery, 2022
Yunxia Dong, Ling Zhou, Zijun Shen, Qingming Ma, Yifan Zhao, Yong Sun, Jie Cao
In the past five decades, anticancer drugs have been used extensively in cancer therapy. However, tumor hypoxia cells show distinct resistance to conventional chemotherapeutic agents, which results in incomplete therapeutic efficacy and tumor recurrence (Zhang et al., 2018; Nagata et al., 2020). Hypoxic reactive drugs, such as tirapamide (TPZ), TH-302, PR-104A, and benzoate (AQ4N), have been demonstrated to provide high select cytotoxicity toward hypoxic mammalian cells (Zhang et al., 2018; Deng et al., 2019; He et al., 2019; Li et al., 2019; Ma et al., 2019; Chen et al., 2021). Among them, tirapazamine (TPZ) is a novel class of bioreductive drugs that can be metabolized to produce free radicals in the presence of anoxic cells, resulting in DNA damage and cell death. Currently, it is often used as a radiosensitizer and combined with cisplatin to treat tumors in the head, neck, lungs, and throat (Kaneda et al., 2019; Wang et al., 2019; Zhao et al., 2020). However, when used alone, the anti-tumor effect of TPZ is largely limited due to the insufficient toxic substances production in oxygen-relative enriched tumor cells in the vicinity of the tumor vessel (Baker et al., 2013). Therefore, creating a hypoxia environment in tumor sites is essential for enhancing the anticancer efficacy of TPZ.
Biomarkers for translational oncology – Peggy Olive’s contribution
Published in International Journal of Radiation Biology, 2022
Applications of the comet assay for measuring tumor hypoxia and drug modifications in patients breathing high oxygen content gases during irradiation (Partridge et al. 2001) and those receiving the blood flow modifying drug nicotinamide were soon reported (McLaren1997). The assay was employed in the clinic in combination with tirapazamine to identify the cells that were the targets for this therapy thus providing a method of identifying those tumors likely to respond to this drug (Dorie et al. 1999). In one study, fine-needle aspiration biopsy (FNAB) was carried out in73 patients with accessible metastatic tumors undergoing palliative radiotherapy for advanced disease. Frequency histograms for tail moment that clearly differentiated aerobic and hypoxic populations were analyzed and hypoxic cells were identified in the majority of FNABs from advanced metastatic tumors. Approximately 62% of 73 advanced tumors showed evidence of hypoxic cells when analyzed by the alkaline comet assay (Olive et al. 1999). Another study demonstrated the application of the comet assay as a good predictive measure of bladder cancer cell radiosensitivity (Moneef et al. 2003).
Usefulness of combination with both continuous administration of hypoxic cytotoxin and mild temperature hyperthermia in boron neutron capture therapy in terms of local tumor response and lung metastatic potential
Published in International Journal of Radiation Biology, 2019
Shin-ichiro Masunaga, Yoshinori Sakurai, Hiroki Tanaka, Takushi Takata, Minoru Suzuki, Yu Sanada, Keizo Tano, Akira Maruhashi, Koji Ono
The development of bioreductive agents that are particularly toxic to hypoxic cells has been considered a promising approach to solving the problem of radio-resistant tumor hypoxia in cancer radiotherapy (Vaupel and Kelleher 2010; Dewhirst et al. 2016; Masunaga 2016). Tirapazamine (TPZ), a leading compound in the development of bioreductive hypoxic cytotoxins, in combination with radiation has been shown to be useful for controlling solid tumors as a whole, especially for controlling quiescent (Q) tumor cell populations that are rich in hypoxic region (Masunaga et al. 2007). Tumor hypoxia results from either limited oxygen diffusion (chronic hypoxia) or limited perfusion (acute hypoxia, transient hypoxia, or ischemic hypoxia) (Brown 1979). Chronically hypoxic tumor cells existing at the rim of the oxygen diffusion distance can be killed by just a single administration of TPZ (Masunaga et al. 2007). Acutely hypoxic tumor cells occurring sporadically throughout solid tumors can be killed by TPZ during long-term continuous administration. Namely, the long-term continuous administration of TPZ can kill both chronically and acutely hypoxic tumor cells (Masunaga et al. 2005).