Abstract

The goal of this research is to develop mechanism-based selective therapy for the treatment of HNSCC. Hypotheses: 1) Delineation of mechanism(s) of actions of ZD1694 should provide the basis for the design of mechanism-based drug sequence for optimal therapeutic benefit. 2) Higher therapeutic index and cure rate can be achieved with ZD1694 and CPT-11 used in sequence than in combination. Cell lines representing poorly differentiated SCC of the pharynx (FaDu) and a well-differentiated epidermoid carcinoma of the neck (A253), will be utilized to carry out the studies outlined.
Specific Aims : 1) Verify that mechanisms associated with in vitro cytotoxicity to ZD1694 and the synergistic interaction between ZD1694 and SN38, an active metabolite of CPT-11, are predictive for in vivo therapeutic selectivity. 2) Evaluate the effect of circulating thymidine on the mechanism of action of ZD1694. 3) Establish that the synergistic interaction achieved in vitro between ZD1694 and SN38 are paralleled by sequential combinations with higher therapeutic index and cure rate. The proposed studies are expected to provide a rational basis for the design of clinical protocols in head and neck cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA065761-04
Application #
2696929
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Wolpert, Mary K
Project Start
1995-07-11
Project End
2001-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263

  Publications

Azrak, Rami G; Cao, Shousong; Pendyala, Lakshmi et al. (2007) Efficacy of increasing the therapeutic index of irinotecan, plasma and tissue selenium concentrations is methylselenocysteine dose dependent. Biochem Pharmacol 73:1280-7
Azrak, Rami G; Frank, Cheryl L; Ling, Xiang et al. (2006) The mechanism of methylselenocysteine and docetaxel synergistic activity in prostate cancer cells. Mol Cancer Ther 5:2540-8
Yin, M-B; Li, Z-R; Toth, K et al. (2006) Potentiation of irinotecan sensitivity by Se-methylselenocysteine in an in vivo tumor model is associated with downregulation of cyclooxygenase-2, inducible nitric oxide synthase, and hypoxia-inducible factor 1alpha expression, resulting in reduced angiog Oncogene 25:2509-19
Rustum, Youcef M (2004) Thymidylate synthase: a critical target in cancer therapy? Front Biosci 9:2467-73
Yin, Ming-Biao; Li, Zhan-Rong; Cao, Shousong et al. (2004) Enhanced 7-ethyl-10-hydroxycamptothecin (SN-38) lethality by methylselenocysteine is associated with Chk2 phosphorylation at threonine-68 and down-regulation of Cdc6 expression. Mol Pharmacol 66:153-60
Faessel, Helene M; Slocum, Harry K; Rustum, Youcef M et al. (2003) Thymidine and hypoxanthine protection patterns of the folic acid-enhanced synergies for combinations of trimetrexate plus a polyglutamylatable inhibitor of purine or thymidylate synthesis against human ileocecal HCT-8 cells. Int J Oncol 23:401-9
Tewes, M; Schleucher, N; Achterrath, W et al. (2003) Capecitabine and irinotecan as first-line chemotherapy in patients with metastatic colorectal cancer: results of an extended phase I study. Ann Oncol 14:1442-8
Wu, Jiaxi; Yin, Ming-biao; Hapke, Gunnar et al. (2002) Induction of biphasic DNA double strand breaks and activation of multiple repair protein complexes by DNA topoisomerase I drug 7-ethyl-10-hydroxy-camptothecin. Mol Pharmacol 61:742-8
Yin, Ming-biao; Hapke, Gunnar; Wu, Jiaxi et al. (2002) Chk1 signaling pathways that mediated G(2)M checkpoint in relation to the cellular resistance to the novel topoisomerase I poison BNP1350. Biochem Biophys Res Commun 295:435-44
Hapke, Gunnar; Yin, Ming-Biao; Wu, Jiaxi et al. (2002) Phosphorylation of chk1 at serine-345 affected by topoisomerase I poison SN-38. Int J Oncol 21:1059-66

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