The overall goal of this project is to perform translational studies with a new and highly effective hypoxic cytotoxin, PR-104, particularly in evaluating its potential for combination with radiotherapy and chemotherapy. PR-104 is a dinitrobenzamide mustards (DNBM) recently developed by our collaborators, Drs. Denny and Wilson at the University of Auckland, which has improved properties over the current prototype of a hypoxic cytotoxin, tirapazamine (TPZ), including a substantial bystander killing that gives it activity against aerobic as well as hypoxic cells in solid tumors. It is expected to enter Phase 1 trials as a single agent in the US, Australia and New Zealand in December 2005/January 2006. The benefit of combining a hypoxic cytotoxin with conventional anticancer therapy is based on the fact that most human solid tumors have regions at low oxygen levels (hypoxia) and the cells in these regions are resistant to killing by radiation and many chemotherapeutic drugs. TPZ has already demonstrated considerable clinical benefit in combination with radiotherapy and cisplatin based chemotherapy. Our preliminary studies show that PR- 104 is superior to TPZ in combination with fractionated radiation with two different human tumor xenografts as well as having substantial single agent activity. We will focus on head and neck cancer, as this is the ideal site for combining a hypoxic cytotoxin with radiotherapy and chemotherapy. The tumor efficacy studies will be performed with several different human head and neck tumor xenografts with PR-104 in parallel with TPZ in order to compare their relative efficacies in a number of different situations! Our specific aims are 1) to determine whether DNA interstrand crosslinks measured by the comet assay can be used as a surrogate marker for activity of PR-104 that could be used in the clinic, 2) to assay the efficacy of PR-104 in combination with fractionated irradiation in a variety of human head and neck cancer xenografts, 3) to determine the extent to which the activity of PR-104 depends on tumor hypoxia, and 4) to determine the extent to which PR-104 potentiates the activity of the most important anticancer drugs used in head and neck cancer. This project has direct applicability to human health: its rationale is the same as that of TPZ, the first hypoxic cytotoxin to show clinical benefit, yet could be substantially superior to TPZ, and therefore has the strong potential of improving human cancer cure rates to a greater extent than does TPZ. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Radiation Therapeutics and Biology Study Section (RTB)
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Stone, Helen B
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Stanford University
Schools of Medicine
United States
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Brown, J Martin; Diehn, Maximilian; Loo Jr, Billy W (2010) Stereotactic ablative radiotherapy should be combined with a hypoxic cell radiosensitizer. Int J Radiat Oncol Biol Phys 78:323-7
Chernikova, Sophia B; Dorth, Jennifer A; Razorenova, Olga V et al. (2010) Deficiency in Bre1 impairs homologous recombination repair and cell cycle checkpoint response to radiation damage in mammalian cells. Radiat Res 174:558-65
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Singleton, Rachelle S; Guise, Christopher P; Ferry, Dianne M et al. (2009) DNA cross-links in human tumor cells exposed to the prodrug PR-104A: relationships to hypoxia, bioreductive metabolism, and cytotoxicity. Cancer Res 69:3884-91
Brown, Martin (2008) What causes the radiation gastrointestinal syndrome?: overview. Int J Radiat Oncol Biol Phys 70:799-800
Ahn, G-One; Brown, J Martin (2008) Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell 13:193-205
Brown, J Martin; Koong, Albert C (2008) High-dose single-fraction radiotherapy: exploiting a new biology? Int J Radiat Oncol Biol Phys 71:324-5