Hypoxia of human solid tumors is associated with reduced cure rates with radiotherapy and with and with increased distant metastases. However, hypoxia also represents an attractive therapeutic target, since drugs can be designed that are activated to become cytotoxic only in the hypoxic environment as solid tumors. The first such drug to enter clinical trial based on this rationale is tirapazamine (TPZ), and it has already demonstrated efficacy in Phase II and III trials with cisplatin in patients with non-small cell lung cancer. TPZ, however, is limited in efficacy, particularly with fractionated irradiation by systemic toxicity. We have recently discovered that the enzymes probably responsible for anti-tumor efficacy and for systemic toxicity are different and occur in different cellular components. This provides a powerful biological rationale for developing new analogs with increased anti-tumor efficacy and reduced systemic toxicity Project 2 will perform studies on the TPZ analogs synthesized in Project 1 and will combine the data with data from Project 3 test hypotheses involved in the development of superior second generation TPZ analogs for combination, radiotherapy, and with cisplatin. We will test the hypothesis that targeting of compounds to DNA, or having them with high metabolism by the nuclear matrix enzyme(s), will improve their hypoxic cytotoxicities and reduce the effects on mitochondria, the latter probably being responsible for the dose-limiting toxicity of TPZ with fractionated irradiation. We will use both mouse and human cells in vitro to measure the aerobic and hypoxic cytotoxicities of the compounds, their potentiation of cisplatin cytotoxicity, their metabolism by the purified nuclear matrix enzyme complex and by mitochondria, and also measure with tumors in vivo the potentiation form both single and fractionated doses of irradiation and of single doses of cisplatin. Data from Project 3, particularly on the diffusability through multicellular layers and the in vivo pharmacokinetics of the drugs, will allow the hypothesis to be tested that anti-tumor efficacy on the differential hypoxic cytotoxicities of the compounds.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA082566-03
Application #
6576554
Study Section
Subcommittee E - Prevention &Control (NCI)
Project Start
2002-04-01
Project End
2003-03-31
Budget Start
Budget End
Support Year
3
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Brown, Martin; Bernhard, Eric; Mitchel, James et al. (2016) Fractionated Radiation for Newly Diagnosed Supratentorial Glioblastoma Multiforme: In Regard to Brachman et al. Int J Radiat Oncol Biol Phys 94:210-211
Bonnet, Muriel; Flanagan, Jack U; Chan, Denise A et al. (2014) Identifying novel targets in renal cell carcinoma: design and synthesis of affinity chromatography reagents. Bioorg Med Chem 22:711-20
Chan, Denise A; Sutphin, Patrick D; Nguyen, Phuong et al. (2011) Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci Transl Med 3:94ra70
Bonnet, Muriel; Flanagan, Jack U; Chan, Denise A et al. (2011) SAR studies of 4-pyridyl heterocyclic anilines that selectively induce autophagic cell death in von Hippel-Lindau-deficient renal cell carcinoma cells. Bioorg Med Chem 19:3347-56
Hicks, Kevin O; Siim, Bronwyn G; Jaiswal, Jagdish K et al. (2010) Pharmacokinetic/pharmacodynamic modeling identifies SN30000 and SN29751 as tirapazamine analogues with improved tissue penetration and hypoxic cell killing in tumors. Clin Cancer Res 16:4946-57
Hay, Michael P; Turcotte, Sandra; Flanagan, Jack U et al. (2010) 4-Pyridylanilinothiazoles that selectively target von Hippel-Lindau deficient renal cell carcinoma cells by inducing autophagic cell death. J Med Chem 53:787-97
Turcotte, Sandra; Giaccia, Amato J (2010) Targeting cancer cells through autophagy for anticancer therapy. Curr Opin Cell Biol 22:246-51
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
Shinde, Sujata S; Maroz, Andrej; Hay, Michael P et al. (2009) One-electron reduction potential of the neutral guanyl radical in the GC base pair of duplex DNA. J Am Chem Soc 131:5203-7
Turcotte, Sandra; Sutphin, Patrick D; Giaccia, Amato J (2008) Targeted therapy for the loss of von Hippel-Lindau in renal cell carcinoma: a novel molecule that induces autophagic cell death. Autophagy 4:944-6

Showing the most recent 10 out of 41 publications