BIOCHEMICAL MODULATION OF DRUG RESISTANCE IN TUMOR CELLS

这一建议的长远目标是开发和研究 显示出协同作用的抗肿瘤药物组合 肿瘤生化调节的抗肿瘤活性 回应。这项研究将集中在临床上有用的抗心磷脂 已知能产生不同类型DNA的肿瘤制剂 损坏。它将这些药物与其他药物结合起来，这些药物可以 抑制DNA修复过程，使肿瘤细胞对 单身特工独自一人。实验将在以下情况下进行 体外培养的人肿瘤细胞，并成功组合 然后将对人类异种移植瘤进行测试，确定 来自培养的细胞系，在裸鼠身上。在活体内 检测，峰值血浆药物水平将被确定，以确保 这种药物水平在人类身上是可以达到的。此外，在 动物研究，肿瘤标本将被检查以 确定DNA修复系统是否已被抑制。药效 成功对抗异种移植瘤的方案将是 在未来发展成临床方案。这种药 将研究的组合包括：(1) 链脲佐菌素/BCNU用于抑制DNA的方案 修复酶0-6烷基鸟嘌呤DNA烷基转移酶，可能 保护大多数人类肿瘤免受DNA的形成 BCNU产生的链间交联物；(2)DNA切除 修复抑制剂阿糖胞苷和羟基脲(HU)联合应用 DDP或新的铂类似物CBDCA，以确定是否 抑制DNA修复可提高DNA水平 由这些制剂产生的交联剂，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 抑制剂与其他DNA交联剂的组合 DDP或CBDCA，以及临床表现令人印象深刻的VP-16 功效。然而，这种功效的机制还没有 之前就有过报道。我们的研究将探索 VP-16致染色质失稳可提高DNA水平 顺铂产生的损害，或降低肿瘤细胞的能力 修复顺铂诱导的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.