PROLIFERATION TARGETED THERAPY IN CARCINOMA OF CERVIX

有大量的实验室和临床证据表明 在典型的7周病程中肿瘤克隆体的重新聚集 宫颈癌的放射治疗效果不佳 肿瘤控制。宫颈癌术后盆腔功能衰竭的发生率 放射治疗从30%到90%的中晚期 肿瘤，人口再增加可能是造成这一糟糕结果的原因。 显然，在这方面需要创新的治疗方法 通常控制不佳的影响女性的疾病。这 拟议的临床研究将测试临床可行性 通过递送来靶向宫颈癌的再种群 多分割放射治疗中的抗增殖治疗 治疗，目的是改善骨盆控制。这一概念 在放射治疗过程中调节肿瘤增殖是一种新的方法 该方法以前未在 临床环境。临床前数据表明羟基脲 (HU)，当长期处于低水平时，临床上可达到 浓度，显著抑制肿瘤细胞的生长。中转 经S时相延长，同时产生较小的细胞杀伤力 或在相对较低浓度的100- 需要150年。使用这种药剂作为抗增殖剂 在放射治疗期间被提出。羟基脲特别是 被选中是因为它作为一种抗增殖剂的有效性， 它适合于口服给药，而且众所周知 来自不同医疗用途的药理概况。这一阶段 我的临床研究建议将确定口服的剂量 给予羟基脲所需的TID，以产生定义的 肿瘤增殖率下降的程度并将决定 该水平在交付时是否具有可接受的毒性 在放射治疗期间同时进行。这项研究将 在每个患者的肿瘤中利用药物诱导的增殖性变化 作为确定抗增殖剂的中间终点 疗效达到的药物血清水平，并将决定 当这些药物水平为 随后在整个放射治疗过程中维持。

There is substantial laboratory and clinical evidence that repopulation of tumor clonogens during a typical 7 week course of radiation therapy for carcinomas of the cervix contributes to poor tumor control. Pelvic failure rates for cervical carcinoma after radiation therapy range from 30-90% for intermediate to advanced tumors, with repopulation likely contributing to this poor outcome. There is clearly a need for innovative treatment approaches in this disease affecting women that is often poorly controlled. This proposed clinical study will test the clinical feasibility of targeting repopulation in cervical carcinoma by delivering antiproliferative therapy during multi-fractionated radiation therapy, with the goal of improving pelvic control. The concept of modulating tumor proliferation during radiotherapy is a novel approach which has not been prospectively tested previously in a clinical setting. The pre-clinical data indicate that hydroxyurea (HU), when present chronically in low, clinically achievable concentrations, significantly inhibits tumor cell growth. Transit through S phase is prolonged, while producing little cell lethality or readiosensitization at the relatively low concentrations of 100- 150Ym required. Use of this agent as a antiproliferative agent during radiation therapy is proposed. Hydroxyurea is specifically selected because of its effectiveness as an antiproliferative agent, its suitability for oral administration, and its well known pharmacologic profile derived from various medical uses. The phase I clinical study proposed will determine the dose of orally administered hydroxyurea given TID required to produce a defined degree of reduction in tumor proliferation rate and will determine whether that level has acceptable toxicity when delivered concurrently for the duration of radiation therapy. The study will utilize drug-induced proliferative changes in each patient's tumor as an intermediate endpoint to determine the antiproliferative efficacy of the drug serum level attained, and will determine toxicities and tumor response when these drug levels are subsequently maintained during a full course of radiotherapy.