The long term objective of this grant is to understand at the cellular and molecular level the mechanism for both the specific toxicity of tirapazamine (TPZ) for hypoxic cells and for its effects on aerobic cells that may be associated with some of its clinical side effects. These side effects include muscle cramping and a general fatigue after repeated administration of TPZ. The basis for the specific antitumor effects of this drug is its ability to be metabolized to a highly toxic radical within hypoxic cells in solid tumors. These cells are considered to be a problem in cancer treatment of solid tumors, both by radiotherapy and chemotherapy. Killing these cells at doses that are not toxic to well-oxygenated cells provides the basis for increasing the efficacy of standard anticancer therapy. Phase II and III trials of this drug are currently in progress, but the frequency of administration of the drug with radiotherapy is limited by its side effects. This laboratory proposes to investigate two new hypotheses relating to the mechanism to hypoxic cytotoxicity of TPZ and muscle cramps. First, they propose that the enzyme responsible for the intracellular metabolism of TPZ is located close to the nuclear matrix and preferentially damages DNA close to these regions. The second hypothesis is that the effects on muscles are a consequence of preferential damage under aerobic conditions to mitochondria, which destroys their normal transmembrane potential, thereby inhibiting ATP production. They will investigate these two hypotheses by determining the enzyme(s) responsible for the intranuclear TPZ metabolism using an in vitro assay of TPZ metabolism, and will determine whether DNA protein crosslinks formed by TPZ under hypoxia are made preferentially to the nuclear matrix. Loss of the transmembrane mitochondrial potential will be investigated using Rh123 accumulation in cells in vitro and in tissues in mice. Since it is likely that the mitochondrial damage is produced by OH radicals produced by the Fenton reaction, the researchers will inhibit this reaction using clinically used iron chelators. These investigations should lead to a better ability to select patients for TPZ administration and to allow more frequent administration of drug by reducing its side effects. In this way the researchers expect to increase the clinical efficacy of this new anticancer agent.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA015201-25
Application #
2683396
Study Section
Radiation Study Section (RAD)
Program Officer
Mahoney, Francis J
Project Start
1978-12-01
Project End
2000-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
25
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Stanford University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Brown, Martin (2010) Henry S. Kaplan Distinguished Scientist Award Lecture 2007. The remarkable yin and yang of tumour hypoxia. Int J Radiat Biol 86:907-17
Brown, J Martin (2002) Tumor microenvironment and the response to anticancer therapy. Cancer Biol Ther 1:453-8
Peters, Katherine B; Brown, J Martin (2002) Tirapazamine: a hypoxia-activated topoisomerase II poison. Cancer Res 62:5248-53
Birrell, Geoff W; Brown, James A; Wu, H Irene et al. (2002) Transcriptional response of Saccharomyces cerevisiae to DNA-damaging agents does not identify the genes that protect against these agents. Proc Natl Acad Sci U S A 99:8778-83
Delahoussaye, Y M; Evans, J W; Brown, J M (2001) Metabolism of tirapazamine by multiple reductases in the nucleus. Biochem Pharmacol 62:1201-9
Birrell, G W; Giaever, G; Chu, A M et al. (2001) A genome-wide screen in Saccharomyces cerevisiae for genes affecting UV radiation sensitivity. Proc Natl Acad Sci U S A 98:12608-13
Brown, J M (2001) Therapeutic targets in radiotherapy. Int J Radiat Oncol Biol Phys 49:319-26
Peters, K B; Wang, H; Brown, J M et al. (2001) Inhibition of DNA replication by tirapazamine. Cancer Res 61:5425-31
Wouters, B G; Delahoussaye, Y M; Evans, J W et al. (2001) Mitochondrial dysfunction after aerobic exposure to the hypoxic cytotoxin tirapazamine. Cancer Res 61:145-52
Bernhard, E J; Mitchell, J B; Deen, D et al. (2000) Re-evaluating gadolinium(III) texaphyrin as a radiosensitizing agent. Cancer Res 60:86-91

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