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Tirapazamine: a bioreductive anticancer drug that exploits tumour hypoxia
1Auckland Cancer Society Research Centre, Faculty of Medicine and Health Science, The University of Auckland, Private Bag 92019, Auckland 1000, New Zealand. b.denny@auckland.ac.nz
Abstract:
Tirapazamine is the second clinical anticancer drug (after porfiromycin) that functions primarily as a hypoxia-selective cytotoxin. Hypoxic cells in tumours are relatively resistant to radiotherapy and to some forms of chemotherapy and are also biologically aggressive, thus representing an important target population in oncology. Tirapazamine undergoes metabolism by reductases to form a transient oxidising radical that can be efficiently scavenged by molecular oxygen in normal tissues to re-form the parent compound. In the absence of oxygen, the oxidising radical abstracts a proton from DNA to form DNA radicals, largely at C4' on the ribose ring. Tirapazamine can also oxidise such DNA radicals to cytotoxic DNA strand breaks. It therefore shows substantial selective cytotoxicity for anoxic cells in culture (typically approximately 100-fold more potent than under oxic conditions) and for the hypoxic subfraction of cells in tumours. Preclinical studies showed enhanced activity of combinations of tirapazamine with radiation (to kill oxygenated cells) and with conventional cytotoxics, especially cisplatin (probably through inhibition of repair of cisplatin DNA cross-links in hypoxic cells). Phase II and III clinical studies of tirapazamine and cisplatin in malignant melanoma and non-small cell lung cancer suggest that the combination is more active than cisplatin alone and preliminary results with advanced squamous cell carcinomas of the head and neck indicate that tirapazamine may enhance the activity of cisplatin with fractionated radiotherapy.
Insights
Tirapazamine is a hypoxia-selective anticancer drug that targets resistant tumor cells. It generates DNA-damaging radicals under low-oxygen conditions, showing promise in combination therapies for various cancers.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Hypoxic tumor cells are resistant to conventional treatments like radiation and chemotherapy.
- Hypoxia is a key factor in tumor aggression and treatment failure.
- Tirapazamine is a hypoxia-selective cytotoxin designed to target these resistant cells.
Purpose of the Study:
- To evaluate tirapazamine as a hypoxia-selective cytotoxin.
- To investigate the efficacy of tirapazamine in combination with radiation and chemotherapy.
- To assess the clinical activity of tirapazamine in various cancer types.
Main Methods:
- Tirapazamine undergoes reductive metabolism to form cytotoxic radicals.
- Selective cytotoxicity was assessed in anoxic versus oxic cell cultures.
- Preclinical studies evaluated combinations with radiation and cisplatin.
- Phase II and III clinical trials were conducted in melanoma, lung, and head and neck cancers.
Main Results:
- Tirapazamine exhibits significantly higher potency against anoxic cells (approx. 100-fold) compared to oxic cells.
- Preclinical data suggested enhanced activity when combined with radiation and cisplatin.
- Clinical studies in melanoma and non-small cell lung cancer indicated improved activity with tirapazamine and cisplatin combination compared to cisplatin alone.
- Preliminary results in head and neck cancers suggest tirapazamine enhances cisplatin activity with radiotherapy.
Conclusions:
- Tirapazamine demonstrates potent selective cytotoxicity against hypoxic tumor cells.
- Combination therapy with tirapazamine shows enhanced efficacy in preclinical and clinical settings.
- Tirapazamine holds potential as an adjunct to standard cancer treatments, particularly for hypoxic tumors.