DNA CONTENT MODULATION BY HPR IN BLADDER TUMORS

维甲酸是维生素A的天然和合成类似物，可以阻止 肿瘤的体外表型表达及抑制生长和诱导 包括膀胱在内的多种动物模型系统的分化 肿瘤。非侵袭性膀胱肿瘤易复发(40%-80%)， 可发生在尿路上皮衬里的任何地方(多时性，视野 效果)。先前对浅表性膀胱癌的初步研究 表明天然或第一代合成维甲酸可能是 在预防复发风险方面很有用，但毒性严重， 剂量限制。芬维甲胺(4-羟基苯基维甲酰胺) 最近开发的合成维甲酸，已被证明是一种有效的 临床前膀胱癌模型中的抗癌药物。此外， 一项大型乳腺癌化学预防试验的初步结果 目前在意大利正在进行的研究表明，该药物耐受性良好。 在拟议的试点研究中，切除浅表肿瘤的患者 尿路上皮检和膀胱镜检查阴性的患者将随机接受4-HPR (2年内每天200毫克)或对照，以评估流量 通过反复冲洗膀胱而产生的细胞学变化。这是一个非 侵入性诊断程序，可频繁重复，并允许 流式细胞术(FCM)快速、客观、可靠的研究 肿瘤DNA含量和增殖活性的定量检测 细胞数量。约50%的有既往病史的患者 浅表肿瘤的DNA含量异常(DNA非整倍体克隆 或S时相分数升高)。根据…… 维甲酸对细胞分化和增殖的活性，似乎 适合研究合成维甲酸4-HPR的能力 调节DNA倍体和增殖。这项研究被设想为一项试点 使用中间终点进行研究，在显示效果的情况下 由化学预防药物，应紧随其后的是III期双剂- 旨在评价4-hpr降低高血压的能力的盲法临床试验 浅表复发和进展为浸润性癌的风险 面临危险的人口。

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.