CHEMOPREVENTION TRIAL OF DIFLUOROMETHYLORNITHINE IN FAMILIAL PROSTATE CANCER

该项目的长期目标是通过阻断多胺合成来防止前列腺癌的发生、促进或进展，从而降低前列腺癌的发病率和死亡率。本研究的主要假设是确定α -二氟甲基鸟氨酸（DFMO），一种酶激活的鸟氨酸脱羧酶（多胺合成的限速步骤）的不可逆抑制剂，是否可以抑制前列腺癌高遗传风险个体前列腺组织中组织多胺含量和进展相关基因。本研究的两个主要具体目标是：(1)在具有早发性前列腺癌家族史（由项目I确定）的先显子的兄弟和近亲男性中进行一项随机、安慰剂对照、双盲IIB期试验。(2)仔细评估DFMO在该人群中的副作用，并将其与对前列腺的生物学效应进行比较。替代终点生物标志物（项目II）将在基线和治疗后（一年后）通过六分仪活检获得的前列腺中进行测量。基线和治疗后游离和总PSA密度也将被测量。将评估与替代终点生物标志物调节的适当相关性。该项目的长期目标是确定抑制前列腺多胺含量是否是预防人类男性前列腺癌的有效策略。

The long-term objective of this Project is to reduce the morbidity and mortality from prostate cancer by preventing its development, promotion, or progression by interrupting polyamine synthesis. The major hypothesis to be tested is to determine whether alpha-difluoromethylornithine (DFMO), an enzyme activated irreversible inhibitor of ornithine decarboxylase (the rate-limiting step of polyamine syntheses), can suppress tissue polyamine content and progression-related genes in prostate tissue of individuals at high genetic risk for prostate cancer. Two major specific aims will be addressed: (1) to conduct a randomized, placebo-controlled, double-blind phase IIB trial of DFMO in bothers and fir-cousin males of probands with familial history of early onset prostate cancer (identified by Project I). (2) to carefully assess the side effects of DFMO in this population and to compare them to the biological effects on the prostate gland. Surrogate endpoint biomarkers (Project II) will be measured in the prostate gland obtained by sextant biopsy at baseline and post-treatment (after one year). Baseline and post-treatment free and total PSA density will also be measured. Appropriate correlations with modulation of surrogate endpoint biomarkers will be assessed. The long-term goal of the Project is to determine if suppression of prostate polyamine contents is an effective strategy for prevention of prostate cancer in human males.