DNA CONTENT MODULATION BY HPR IN BLADDER TUMORS

维生素A的天然和合成类似物维甲酸，可以阻断 表型表达的癌症，并可以抑制生长和诱导 分化在许多动物模型系统，包括膀胱 肿瘤的 非侵袭性膀胱肿瘤容易复发（40-80%）， 可发生在尿路上皮的任何部位（多时性，视野 效果）。 先前在浅表性膀胱肿瘤中的初步研究 表明天然或第一代合成类维生素A可能是 有助于防止复发的风险，但毒性严重， 剂量限制。 芬维A胺（4-羟基苯基维A酰胺）（4-HPR），一种更 最近开发的合成类维生素A，已被证明是一种有效的 在临床前膀胱癌模型中的抗癌剂。 此外，委员会认为， 一项大型乳腺癌化学预防试验的初步结果 目前在意大利进行的研究表明，该药物耐受性良好。 在拟议的初步研究中，切除浅表肿瘤的患者 将尿路上皮和膀胱镜检查阴性患者随机分配至4-HPR组 (200 mg/天，持续2年）或对照组，以评估流量 通过反复膀胱冲洗的细胞计数变化。 这是非 侵入性诊断程序，可以经常重复，并允许 流式细胞术（FCM）的可靠研究，用于快速，客观 定量肿瘤的DNA含量和增殖活性 细胞群 约50%的患者有既往病史 浅表肿瘤具有异常的DNA含量（DNA非整倍体克隆 或升高的S期分数）。 鉴于 类维生素A对细胞分化和增殖的活性， 适合研究合成类维生素A 4-HPR的能力， 调节DNA倍性和增殖。 这项研究被认为是一项试点研究， 具有中间终点的研究，在已证实效果的情况下， 第三阶段的化学预防剂，应遵循双- 一项旨在评估4-HPR降低 浅表复发和进展为浸润性癌症的风险 人口处于危险之中。

Retinoids, the natural and synthetic analogs of vitamin A, can block the phenotypic expression of cancer in vitro and can inhibit growth and induce differentiation in many animal model systems, including urinary bladder tumors. Noninvasive bladder tumors are prone to recurrence (40-80%), which can occur anywhere in the urothelial lining (polychronotropism, field effect). Previous pilot studies in superficial bladder tumors have suggested that natural or first-generation synthetic retinoids might be useful in preventing the risk of recurrence, but toxicity was severe and dose limiting. Fenretinide (4-hydroxyphenylretinamide) (4-HPR), a more recently developed synthetic retinoid, has shown to be a potent anticarcinogenetic agent in preclinical bladder cancer models. Moreover, preliminary results of a large breast cancer chemopreventive trial currently in progress in Italy have shown that the drug is well tolerated. In the proposed pilot study, patients with resected superficial tumors of the urothelial tract and negative cystoscopy will be randomized to 4-HPR (200 mg day for 2 years) or control in order to evaluate the flow cytometric variations through repeated bladder washings. This is a non invasive diagnostic procedure which can be frequently repeated and allows reliable studies of flow cytometry (FCM) for a rapid and objective quantitation of the DNA content and proliferative activity of the tumor cell population. About 50% of patients with previous history of superficial tumors have abnormal DNA content (either DNA aneuploid clones or elevated S phase fraction) in absence of visible lesions. In light of the retinoid activity on cell differentiation and proliferation, it seems appropriate to study the ability of the synthetic retinoid 4-HPR to modulate DNA ploidy and proliferation. the study is conceived as a pilot study with intermediate end-points, which, in case of demonstrated effects by the chemopreventive agent, should be followed by a phase III double- blind clinical trial aimed at evaluating the ability of 4-HPR to reduce the risk of superficial recurrence and progression to invasive cancer in a population at risk.