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.
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