GYNECOLOGIC MALIGNANCIES--NOVEL PHASE II AGENTS

这一建议的总体目标是进行小说的第二阶段研究， 药物在妇科恶性肿瘤患者中的应用 总部设在纽约的多机构联合会，纽约妇科 肿瘤组（纽约GOG）。具体而言，该提案将侧重于审判 新的类维生素A（R）+干扰素（IFN）的组合在患有 局部晚期或晚期宫颈癌和拓扑异构酶I 难治性卵巢癌患者中的抑制剂， 确定活性方案并表征这些方案的毒性， 养生法纽约州政府非常适合开展此类研究，因为： 妇科肿瘤学家、医学 肿瘤学家、放射肿瘤学家和附属实验室科学家; 宫颈癌和卵巢癌患者人数众多， 本财团;和以前的跟踪记录的快速增长，这样的 问题研究纽约GOG将每年开展2-3项II期研究。纽约的 GOG目前正在进行一项基于实验室的II期全反式 维甲酸（RA）+干扰素治疗晚期宫颈癌， 将作为R + IFN II期研究的模型，纽约 纽约大学（NYU）目前正在进行新的II期试验， 拓扑异构酶-L抑制剂的时间表，这将是模型的建议， 卵巢癌的临床试验四个实验室子项目将提供 相关信息，这将有助于指导进一步 这些疗法的发展。在分项目1中，聚合酶链反应 技术将用于检测和分型人乳头瘤病毒（HPV） 在来自用R + IFN治疗的患者的活检标本中。在次级项目2中， 将进行药代动力学研究以测量R水平， 急性和慢性。在子项目3中， 受体（RAR α、RAR β、RAR γ和RAR XR）和细胞质视黄酸 结合蛋白（CRABP 1和II）将在活组织检查标本中测量。在 子项目4，卵巢组织中Topo-L的水平将通过 Western印迹这些实验室检测的结果将与 对治疗的反应、反应持续时间和临床结果 参加这些试验的患者的目标是确定 可能从这些治疗中受益的患者亚群 联合用药，并指导未来方案的开发。

The overall aims of this proposal are to conduct phase Il studies of novel agents in patients with gynecologic malignancies through a multiinsitutional consortium based in New York, the New York Gynecologic Oncology Group (NY GOG). Specifically this proposal will focus on trials of combinations of novel retinoids (R) + interferon (IFN) in patients with locally advanced or advanced cervix cancer and on topoisomerase-I inhibitors in patients with refractory ovarian carcinoma with the goal of identifying active regimens and characterizing the toxicities of these regimens. The NY GOG is well-suited to carry out such studies because of: the close collaboration between Gynecologic Oncologists, Medical Oncologists, Radiation Oncologists, and affiliated laboratory scientists; the large population base with both cervical and ovarian cancers served by this Consortium; and a previous track-record of rapid accrual to such studies. The NY GOG will carry out 2-3 phase II studies per year. The NY GOG is currently performing a laboratory-based phase Il trial of all-trans retinoic acid (RA) + IFN in patients with advanced cervix cancer which will serve as a model for the phase Il studies of R + IFN, and New York University (NYU) is currently performing phase Il trials of novel schedules of topo-l inhibitors which will be models for the proposed trials in ovarian cancer. Four laboratory subprojects will provide correlative information which will be useful in guiding the further development of these therapies. In subproject 1, polymerase chain reaction technology will be employed to detect and type human papillomavirus (HPV) in biopsy specimens from patients treated with R + IFN. In subproject 2, pharmacokinetic studies will be performed to measure levels of R both acutely and chronically. In subproject 3, levels of mRNA for retinoic acid receptors (RARalpha, -beta, -gamma, and RXR) and cytoplasmic retinoic acid binding proteins (CRABP l and II) will be measured in biopsy specimens. In subproject 4, levels of topo-l will be assayed in ovarian tissue by Western blot. The results of these laboratory assays will be correlated with response to therapy, response duration, and clinical outcome of patients entered on these trials with the goals of determining subpopulations of patients likely to benefit from treatment with these combinations and to guide development of future regimens.