POLYAMINE MODULATION OF SQUAMOUS CANCER GROWTH KINETICS

放射治疗是鳞状细胞癌的主要治疗手段 (SCCS)头颈部(H&N)区域(即舌头、咽、喉)。 实验室和临床数据现在表明，存活的 常规7-9周根治性H&N疗程中的肿瘤克隆性 由于肿瘤迅速再生长，放射治疗损害了肿瘤控制 治疗过程中的克隆菌。应用流式细胞术进行肿瘤动力学分析 确认H&N细胞的克隆倍增时间在 最快的人类实体肿瘤，中位数潜在倍增时间 (Tpot)4-5天。强化放射治疗分割计划 在缩短的总体治疗时间内提供一种方法 对抗这一肿瘤克隆原再繁殖问题的方法。几个 这种加速治疗方案正成功地应用于H&N 全球癌症患者局部区域肿瘤控制率提高， 但随着急性治疗毒性的显著增加。 寻找快速克隆原的另一种生物学方法 再繁殖问题涉及到对肿瘤生长动力学的操纵 在放射治疗过程中，而不是强化 物理辐射治疗参数。这项提议的目的是 因此要研究抗增殖剂的能力 参与多胺代谢以减缓人类肿瘤生长动力学 H&N的SCCS用于研究的特定药物包括多胺 生物合成抑制剂α-二氟甲基鸟氨酸(DFMO) 合成多胺类似物1，19-双(乙氨基)-5，10，15- 三氮杂十一烷(BE-4-4-4-4)和N，N-双[3-乙氨基]-1，7- 肝二胺(BE-3-7-3)。据推测，这些多胺 途径代谢抑制物，具有降低肿瘤的能力 在根治性放射治疗过程中的增殖率，将提供 一种可以快速实现提高肿瘤控制率的方法 H&N细胞分化的一系列体外流式细胞术动力学研究 研究，体内小鼠异种移植生长研究，和正常粘膜组织 将进行反应研究以检查多胺的作用 肿瘤增殖动力学的调节可能在影响肿瘤生长的过程中发挥作用 人类干细胞的终极放射耐受性。

Radiation is a primary treatment modality for squamous cell carcinomas (SCCs) of the head and neck (H&N) region (ie, tongue, pharynx, larynx). Laboratory and clinical data now indicate that proliferation of surviving tumor clonogens during a conventional 7-9 week course of curative H&N radiotherapy compromises tumor control due to rapid repopulation of tumor clonogens during treatment. Tumor kinetic analysis via flow cytometry confirms that clonogenic doubling times for SCCs of the H&N are among the most rapid of human solid tumors with median potential doubling times (Tpot) of 4-5 days. Intensified radiotherapy fractionation schedules delivered over a reduced overall treatment time provide one method of approach to counteract this tumor clonogen repopulation issue. Several such accelerated treatment regimens are being successfully employed in h&N cancer patients worldwide with improved locoregional tumor control rates, but with markedly increased acute treatment toxicities. An alternative biological method of approach to the rapid clonogen repopulation issue involves the manipulation of tumor growth kinetics during the radiotherapy treatment course, rather than the intensification of physical radiation treatment parameters. The objective of this proposal is therefore to investigate the capacity of antiproliferative agents involved in polyamine metabolism to slow tumor growth kinetics in human SCCs of the H&N. Specific agents for study include the polyamine biosynthesis inhibitor alpha-difluoromethylornithine (DFMO), and the newly synthesized polyamine analogs 1,19-bix-(ethylamino)-5,10,15- traiazanonadecane (BE-4-4-4-4) and N,N-bis[3-(ethylamino)propyl]-1,7- hepatanediamine (BE-3-7-3). It is hypothesized that these polyamine pathway metabolic inhibitors, with the capacity to decrease tumor proliferation rate during a course of curative radiotherapy, will provide a method whereby improved tumor control rates can be achieved in rapidly dividing SCCs of the H&N. A series of in vitro flow cytometry kinetic studies, in vivo mouse xenograft growth studies, and normal mucosal tissue response studies will be performed to examine the role that polyamine modulation of tumor proliferation kinetics might play in influencing the ultimate radiocurability of human SCCs.