POLYAMINE MODULATION OF SQUAMOUS CANCER GROWTH KINETICS

放射是鳞状细胞癌的主要治疗方式 头颈部（H&N）区域（即舌、咽、喉）的SCC。 实验室和临床数据表明， 在常规的7-9周治疗性H&N过程中的肿瘤克隆原 由于肿瘤的快速再增殖，放射治疗损害了肿瘤控制 在治疗过程中使用克隆原。 通过流式细胞术进行肿瘤动力学分析 证实了H&N的SCC的克隆形成倍增时间是其中之一。 最快速的人类实体瘤，中位潜在倍增时间 （Tpot）4-5天。 强化放疗分次方案 提供了一种方法， 解决这种肿瘤克隆原再增殖问题的方法。 几 这种加速治疗方案正成功地应用于h&N 全世界癌症患者的局部肿瘤控制率得到改善， 但具有显著增加的急性治疗毒性。 快速克隆原的另一种生物学方法 再增殖问题涉及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。 本提案的目的 因此，研究抗增殖剂 参与多胺代谢以减缓人类肿瘤生长动力学 H&N的SCC。 用于研究的特定试剂包括聚胺 生物合成抑制剂α-二氟甲基鸟氨酸（DFMO），以及新的 合成的多胺类似物1，19-bix-（乙氨基）-5，10，15- 三氮杂十九烷（BE-4- 4 - 4-4）和N，N-双[3-（乙氨基）丙基]-1，7- 庚二胺（BE-3-7-3）。 据推测，这些多胺 途径代谢抑制剂，具有降低肿瘤 在治疗性放疗过程中的增殖率，将提供 一种可以快速实现改善的肿瘤控制率的方法， 划分H&N的SCC。 一系列体外流式细胞术动力学 研究、体内小鼠异种移植物生长研究和正常粘膜组织 反应研究将进行检查的作用，多胺， 肿瘤增殖动力学的调节可能在影响 人类SCC的最终辐射可治愈性。

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.