DFMO AND BCNU IN EXPERIMENTAL CHEMOTHERAPY OF CARCINOMA

二氟甲基鸟氨酸(DFMO)诱导多胺的机制 耗竭使人腺癌细胞对 对1，3-二(2-氯乙基)-1-亚硝脲(BCNU)进行了研究。此外, 该药物组合的体内效用将在人体内进行评估 裸鼠体内的腺癌移植瘤。为了调查DNA和 以染色体损伤为靶点的药物相互作用 DFMO处理组和对照组的姐妹染色单体互换 文化。由于O6-烷基鸟嘌呤DNA烷基转移酶被 已知链脲佐菌素(STZ)可增加DNA链间交联。 BCNU耐药细胞，DFMO联合STZ进一步增强细胞毒作用 并将测试交联性。如果DFMO在靶点使细胞对BCNU敏感 除DNA交联物外，NO对细胞毒性的相加效应 在低于最佳剂量的STZ中，应观察到交联度的增加。 不同化学机制对亚硝脲的DFMO增敏作用 将比较行动，以确定DFMO的敏化是否对 氯乙基或BCNU的异氰酸酯部分。如果BCNU诱导的DNA或 在多胺缺乏的细胞中，染色体损伤加剧， 核DNA对DNase-I酶的敏感性将用于研究DFMO 对染色质缩合的影响。调查BCNU目标，而不是 可被DFMO致敏的DNA增加了BCNU介导的细胞裂解 多胺耗竭的细胞将与进一步减少 DFMO预处理后BCNU的克隆形成能力。停用 BCNU的膜转运系统将在多胺耗竭患者中进行比较 并控制文化。BCNU诱导细胞合成的假说 热休克蛋白(由其他毒物诱导并使细胞 耐热杀灭)将进行测试。如果BCNU诱发发热 热休克细胞的休克反应、BCNU敏感性及BCNU诱导 多胺缺乏细胞中热休克的影响将进一步研究。至 荷人腺癌裸鼠体内致敏实验研究 异种移植物将接受BCNU、DFMO或它们的联合治疗。肿瘤 增长将通过销量估计来监控。血液学和肺病学 毒性也将进行评估。如果更多的提高抗肿瘤疗效 如果毒性增加，BCNU的治疗指数可能会提高 采用DFMO进行预处理。

Mechanisms by which yield-difluoromethylornithine (DFMO)-induced polyamine depletion sensitizes human adenocarcinoma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) will be studied. In addition, the in vivo utility of the drug combination will be evaluated using human adenocarcinoma xenografts in athymic (nude) mice. To investigate DNA and chromosomal damage as the target for the drugs' interaction, BCNU-induced sister chromatid exchanges will be measured in DFMO-pretreated and control cultures. Since depletion of O6-alkylguanine DNA alkyltransferase by streptozotocin (STZ) is known to increase DNA interstrand crosslinking in BCNU-resistant cells, further enhancement by DFMO plus STZ of cytotoxicity and crosslinks will be tested. If DFMO sensitizes cells to BCNU at targets other than DNA crosslinks, additive effects on cytotoxicity with no increase in crosslinks should be observed at sub-optimal doses of STZ. DFMO potentiation of nitrosoureas with different chemical mechanisms of action will be compared to determine if sensitization by DFMO is to the chloroethyl or the isocyanate portion of BCNU. If BCNU-induced DNA or chromosomal damage is enhanced in the polyamine-deficient cells, sensitivity of nuclear DNA to DNase-I digestion will be used to study DFMO effects on chromatin condensation. To investigate BCNU targets other than DNA which may be sensitized by DFMO, increased BCNU-mediated cell lysis in polyamine-depleted cells will be distinguished from further reduction of clonogenic potentials by BCNU after DFMO pretreatment. Inactivation of membrane transport systems by BCNU will be compared in polyamine-depleted and control cultures. The hypothesis that BCNU induces synthesis of heat-shock proteins (which are induced by other toxic agents and make cells resistant to thermal killing) will be tested. If BCNU induces the heat shock response, BCNU sensitivity of heat-shocked cells and BCNU induction of heat shock in polyamine-deficient cells will be studied further. To investigate in vivo sensitization, nude mice bearing human adenocarcinoma xenografts will be treated with BCNU, DFMO or their combination. Tumor growth will be monitored by volume estimates. Hematologic and pulmonary toxicity will also be evaluated. If antitumor efficacy is enhanced by more than toxicity is increased, the therapeutic index of BCNU may be improved by DFMO pretreatment.