BIOCHEMICAL MODULATION OF DRUG RESISTANCE IN TUMOR CELLS

该提案的长期目标是开发和研究 抗肿瘤药物组合， 通过肿瘤的生物化学调节的抗肿瘤活性 应答 该研究将集中在临床上有用的抗- 已知产生不同类型DNA的肿瘤因子 损害 它将联合收割机与其他药物， 抑制DNA修复过程，使肿瘤细胞对 单独的特工 实验将在以下条件下进行： 体外培养的人肿瘤细胞，以及成功的组合 然后将针对人类异种移植肿瘤进行测试， 从培养的细胞系，在裸鼠。 在体内 测试，药物的峰值血浆水平将被确定，以确保 药物水平在人体内是可以达到的。 更以 在动物研究中，将检查肿瘤标本， 确定DNA修复系统是否受到抑制 药物 成功对抗异种移植肿瘤的方案将是 在未来发展成临床方案。 药物 将研究的组合包括：（1） 链脲佐菌素/BCNU方案旨在抑制DNA 修复酶0-6烷基鸟嘌呤DNA烷基转移酶，其可以 保护大多数人类肿瘤不形成DNA BCNU产生的链间交联;（2）DNA切除 修复抑制剂Ara-C和羟基脲（HU）与 DDP或新的铂类似物CBDCA，以确定是否 抑制DNA修复可以增加DNA水平， 由这些试剂产生的交联，以及随后的肿瘤 细胞杀伤（未来的研究将继续使用这些DNA修复 抑制剂与其它DNA交联剂的组合， DDP，或CBDCA，和VP-16，已显示出令人印象深刻的临床 功效 然而，这种功效的机制还没有 以前报道过。 我们的研究将探讨 VP-16引起的染色质不稳定可以增加DNA水平， DDP产生的损伤，或降低肿瘤细胞的能力， 修复DDP引起的DNA损伤。

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.