DNA CONTENT MODULATION BY HPR IN BLADDER TUMORS

点击翻译按钮获取中文摘要

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.