One-carbon nutrients in cancer prevention

描述（由申请人提供）：从许多不同类型的科学研究中积累的证据表明，维生素 B 叶酸摄入不足会增加患多种癌症的风险。 结直肠癌的证据最为引人注目。 然而，现有证据表明，叶酸缺乏只有在与其他不明确的遗传和环境易患癌症的因素同时作用时才会导致癌症。 该 K05 应用的首席研究员将其职业生涯的大部分时间投入到研究叶酸与致癌作用之间的关系。 他现在准备开始研究其他几个因素，例如年龄、烟草以及维生素 B6 和 B12 消耗，如何与叶酸代谢相互作用，从而加剧仅叶酸消耗所导致的癌症的发生。 K05 奖项提供的财政资源将使研究者能够免除其医疗中心临床和行政职责的巨大负担，从而使他能够将几乎所有的专业精力投入到阐明上述因素上。 该研究人员还拥有出色的指导记录，并培训了几位年轻人，他们现在自己已经是完全独立的科学家了。 因此，这个奖项将为首席研究员腾出足够的时间，使他能够在未来接受更多的实习生。 旨在解决上述问题的研究包括本质上互补的人体和动物实验。 完善的 B 族维生素消耗、衰老和结直肠癌发生大鼠模型将用于确定 B 族维生素缺乏和老年的哪些组合可以增强叶酸消耗产生的致癌环境，以及这些作用是通过什么机制介导的。 DNA 微阵列技术的使用将阐明以前未曾怀疑的新型癌症途径的鉴定。 一项旨在检查习惯性吸烟者的人体研究将研究吸烟如何改变口腔中这些维生素的代谢，从而增加患口腔癌的风险，以及是否可以通过补充叶酸来改善这种癌症的替代生物标志物。

DESCRIPTION (provided by applicant): Accumulating evidence from many different types of scientific studies indicate that inadequate intake of the B vitamin, folate, increases the risk of several cancers. The evidence is most compelling for cancer of the colorectum. However, the prevailing evidence suggests that folate depletion only results in cancer when it operates in concert with other ill-defined genetic and environmental predispositions to cancer. The principle investigator of this K05 application has devoted the majority of his career to investigating this relationship between folate and carcinogenesis. He is now poised to begin to investigate how several other factors, such as age, tobacco, and vitamin B6 and B12 depletion interact with folate metabolism in such a way as to accentuate the promotion of cancer conveyed by folate depletion alone. The financial resources afforded by this K05 award will enable the investigator to dispense with a very substantial burden of clinical and administrative duties in his medical center, thereby allowing him to devote nearly all of his professional energies towards the elucidation of the factors outlined above. The investigator also has an excellent track record of mentoring and has trained several young people who are now fully independent scientists themselves. This award, therefore, would free up enough of the Principal Investigator's time to enable him to take on additional trainees in the future. The studies that are intended to address the abovementioned issues include human and animal experiments that are complimentary in nature. Well-established rat models of B-vitamin depletion, aging, and colorectal carcinogenesis will be used to define which combinations of B-vitamin deficiencies and elder age can potentiate the procarcinogenic milieu produced by folate depletion, and by what mechanisms these effects are mediated. The identification of novel, previously unsuspected, pathways towards cancer will be elucidated by use of DNA microarray technology. A human study, designed to examine habitual cigarette smokers, will examine how smoking alters the metabolism of these vitamins in the mouth in order to convey an increased risk of oral cancer, and whether surrogate biomarkers of this cancer can be improved by the use of folate supplementation.