Tirapazamine ( SR-4233, WIN 59075) is an experimental anticancer drug that is activated to a toxic radical only at very low levels of

oxygen Oxygen is a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...

( hypoxia). Such levels are common in human solid

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

s, a phenomenon known as tumor hypoxia. Thus, tirapazamine is activated to its toxic form preferentially in the hypoxic areas of solid tumors. Cells in these regions are resistant to killing by

radiotherapy Radiation therapy or radiotherapy (RT, RTx, or XRT) is a treatment using ionizing radiation, generally provided as part of cancer therapy to either kill or control the growth of malignant cells. It is normally delivered by a linear particle ...

and most anticancer drugs. Thus the combination of tirapazamine with conventional anticancer treatments is particularly effective. , tirapazamine is undergoing phase III testing in patients with head and neck cancer and gynecological cancer, and similar trials are being undertaken for other solid tumor types. Chemically it is an aromatic heterocycle di-N-oxide. Its full chemical name is 3-amino-1,2,4-benzotriazine-1,4 dioxide. Originally it was prepared in a program screening for new

herbicide Herbicides (, ), also commonly known as weed killers, are substances used to control undesired plants, also known as weeds.EPA. February 201Pesticides Industry. Sales and Usage 2006 and 2007: Market Estimates. Summary in press releasMain page f ...

s in 1972. Its clinical use was first described by Zeman ''et al.'' in 1986. While tirapazamine has had only limited effectiveness in

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s, it has been used as a lead compound to develop a number of newer compounds with improved anti-cancer properties. An update of a Phase III trial (Tirapazamine,

cisplatin Cisplatin is a chemical compound with chemical formula, formula ''cis''-. It is a coordination complex of platinum that is used as a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, c ...

, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group) found no evidence that the addition of TPZ to chemoradiotherapy, in patients with advanced head and neck cancer not selected for the presence of hypoxia, improved overall survival. Two possible molecular mechanisms of TPZ, for generating reactive oxygen species which causes DNA strand break, have been considered widely. In hypoxia, under bioreductive condition, it has been observed that TPZ primarily produces hydroxyl or and benzotriazinyl radicals as the DNA damaging reactive species. A new clinical phase I trial of Tirapazamine combined with embolization in liver cancer has been received in June, 2014. This study will help to optimize the safe tolerable dose of TPZ, when it is administered with embolization in liver cancer. Treatment of solid tumors is complicated by the fact that these are often poorly provided with blood vessels, thus limiting their exposure to cytotoxic agents. Attempts have, however, been made to take advantage of the resulting hypoxic environment by designing drugs that are nonreactive until they are reduced to reactive species in oxygen-deficient tissues. This, it is hoped, will lead to enhanced selectivity. The azaquinoxaline dioxide function on the antineoplastic agent tirapazamine, for example, has been shown to give reactive nitroxide radicals on reduction.

Synthesis

The condensation of 2-nitroaniline 8-74-4(1) with cyanamide 20-04-2(2) probably initially involves the formation of guanidinonitrobenzene 0973-04-5(3). The very basic

nitrogen Nitrogen is a chemical element; it has Symbol (chemistry), symbol N and atomic number 7. Nitrogen is a Nonmetal (chemistry), nonmetal and the lightest member of pnictogen, group 15 of the periodic table, often called the Pnictogen, pnictogens. ...

in that species then condenses with the adjacent nitro group, closing the ring to give 1,2,4-Benzotriazin-3-amine 1-oxide 424-06-6(4). Oxidation with

hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscosity, viscous than Properties of water, water. It is used as an oxidizer, bleaching agent, and antiseptic, usua ...

then completes the preparation of tirapazamine (5).

References

External links

* {{ClinicalTrialsGov, NCT00033410, Chemotherapy, Tirapazamine, and Radiation Therapy in Treating Patients With Non-Small Cell Lung Cancer Experimental cancer drugs SRI International Amine oxides Heterocyclic compounds with 2 rings Benzotriazines