The long-term goal of this proposal is the development and study of anti-tumor agent combinations that demonstrate synergistic anti-tumor activity by biochemical modulation of tumor responses. The study will concentrate on clinically useful anti- tumor agents which are known to produce varying types of DNA damage. It will combine these agents with other drugs which can inhibit DNA repair processes that make tumor cells resistant to the single agents alone. Experiments will be performed with human tumors cells cultured in vitro, and successful combinations will then be tested against human xenograft tumors, established from the cultured cell lines, in nude mice. During the in vivo testing, peak plasma levels of drugs will be determined to assure that drug levels will be achievable in humans. Furthermore, in the animal studies, tumor specimens will be examined to determine if the DNA repair systems have been inhibited. Drug regimens that are successful against xenograft tumors will be developed into clinical protocols in the future. The drug combinations that will be studied include: (1) Streptozotocin/BCNU in a regimen designed to inhibit the DNA repair enzyme 0-6 alkylguanine DNA alkyltransferase, which may protect a majority of human tumors from the formation of DNA interstrand crosslinks produced by BCNU; (2) the DNA excision repair inhibitors Ara-C and Hydroxyurea (HU) in combination with DDP or the new platinum analog, CBDCA, to determine if inhibition of DNA repair can increase the level of DNA crosslinking produced by these agents, and the subsequent tumor cell kill (future studies will pursue the use of these DNA repair inhibitors with other DNA crosslinking agents such combination of DDP, or CBDCA, and VP-16 which has shown impressive clinical efficacy. However the mechanisms for this efficacy have not been previously reported. Our studies will explore whether or not chromatin destabilization by VP-16 can increase the level of DNA damage produced by DDP, or decrease the tumor cell's ability to repair the DDP-induced DNA damage.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045628-03
Application #
3188762
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1987-07-16
Project End
1992-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Loyola University Chicago
Department
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Zhang, Qiwei; Ohannesian, David W; Erickson, Leonard C (2004) Hammerhead ribozyme-mediated sensitization of human tumor cells after treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea. J Pharmacol Exp Ther 309:506-14
Kreklau, E L; Limp-Foster, M; Liu, N et al. (2001) A novel fluorometric oligonucleotide assay to measure O( 6)-methylguanine DNA methyltransferase, methylpurine DNA glycosylase, 8-oxoguanine DNA glycosylase and abasic endonuclease activities: DNA repair status in human breast carcinoma cells overexpressin Nucleic Acids Res 29:2558-66
Kreklau, E L; Liu, N; Li, Z et al. (2001) Comparison of single- versus double-bolus treatments of O(6)-benzylguanine for depletion of O(6)-methylguanine DNA methyltransferase (MGMT) activity in vivo: development of a novel fluorometric oligonucleotide assay for measurement of MGMT activity. J Pharmacol Exp Ther 297:524-30
Williams, D A; Maze, R; Kurpad, C et al. (2000) Protection of hematopoietic cells against combined O6-benzylguanine and chloroethylnitrosourea treatment by mutant forms of O6-methylguanine DNA methyltransferase. Bone Marrow Transplant 25 Suppl 2:S105-9
Kreklau, E L; Kurpad, C; Williams, D A et al. (1999) Prolonged inhibition of O(6)-methylguanine DNA methyltransferase in human tumor cells by O(6)-benzylguanine in vitro and in vivo. J Pharmacol Exp Ther 291:1269-75
Maze, R; Kurpad, C; Pegg, A E et al. (1999) Retroviral-mediated expression of the P140A, but not P140A/G156A, mutant form of O6-methylguanine DNA methyltransferase protects hematopoietic cells against O6-benzylguanine sensitization to chloroethylnitrosourea treatment. J Pharmacol Exp Ther 290:1467-74
Pieper, R O; Noftz, S L; Erickson, L C (1995) In vitro transcription termination by N,N'-bis(2-chloroethyl)-N-nitrosourea-induced DNA lesions. Mol Pharmacol 47:290-5
Kroes, R A; Erickson, L C (1995) The role of mRNA stability and transcription in O6-methylguanine DNA methyltransferase (MGMT) expression in Mer+ human tumor cells. Carcinogenesis 16:2255-7
Costello, J F; Futscher, B W; Tano, K et al. (1994) Graded methylation in the promoter and body of the O6-methylguanine DNA methyltransferase (MGMT) gene correlates with MGMT expression in human glioma cells. J Biol Chem 269:17228-37
Marathi, U K; Dolan, M E; Erickson, L C (1994) Extended depletion of O6-methylguanine-DNA methyltransferase activity following O6-benzyl-2'-deoxyguanosine or O6-benzylguanine combined with streptozotocin treatment enhances 1,3-bis(2-chloroethyl)-1-nitrosourea cytotoxicity. Cancer Res 54:4371-5

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