Ishii H, Dumon K R, Vecchione A, Fong L Y, Baffa R, Huebner K, Croce C M
Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th St, Philadelphia, PA 19107-5799, USA.
JAMA. 2001 Nov 21;286(19):2441-9. doi: 10.1001/jama.286.19.2441.
The fragile histidine triad gene (FHIT) encompasses a human common fragile site, FRA3B, that is susceptible to environmental carcinogens. Deletion and inactivation of FHIT have been seen in a number of human premalignant and malignant lesions.
To review and evaluate preclinical studies of cancer therapy using the FHIT tumor suppressor gene and related studies involving Fhit protein expression.
A MEDLINE search of articles published from 1996 to June 2001 was performed; article reference lists were used to retrieve additional relevant articles.
Immunohistochemical studies of primary tumors or relevant lesions were selected to evaluate Fhit expression in premalignant or malignant stages. Preclinical studies on antitumorigenic or therapeutic introduction of FHIT were reviewed for the effects of exogenous Fhit expression. For the immunohistochemical analyses, 26 studies were included that analyzed at least 15 cases of a single type of tumor. For precancerous lesions, 9 studies were included that analyzed at least 4 cases. For studies of FHIT introduction, 9 published studies were included.
Using primary data from each of the studies, we assessed the rationale and potential contribution of FHIT cancer therapy. Data was independently abstracted by 2 authors and study quality was assessed by 2 other authors.
Overall, 60% (1162/1948 cases) of primary tumors showed absent or markedly reduced Fhit protein expression in cancer cells. Studies of preneoplastic lesions or early-stage cancer showed absence or marked reduction of Fhit protein expression in 0% to 93% of samples (overall, 31% [127/408 cases]). Preclinical studies using 26 cancer-derived cell lines from human lung, head and neck, esophageal, gastric, cervical, pancreatic, and kidney cancers, showed that reintroduction of FHIT resulted in inhibition of in vitro tumor cell growth or of in vivo tumorigenicity in 17 (57%) of 30 cell line experiments. Model systems for human preventive cancer therapy suggested that oral introduction of viral vector-mediated FHIT into Fhit-deficient mice may prevent carcinogen-induced tumor development in some cases.
These findings show that FHIT gene therapy may potentially be clinically useful for treatment of cancer and also prevention of carcinogen-induced tumor development, suggesting a rationale for further research involving FHIT introduction.
脆性组氨酸三联体基因（FHIT）包含一个人类常见脆性位点FRA3B，该位点易受环境致癌物影响。在许多人类癌前病变和恶性病变中已观察到FHIT基因的缺失和失活。
综述和评估使用FHIT肿瘤抑制基因进行癌症治疗的临床前研究以及涉及Fhit蛋白表达的相关研究。
对1996年至2001年6月发表的文章进行了MEDLINE检索；文章参考文献列表用于检索其他相关文章。
选择对原发性肿瘤或相关病变进行的免疫组织化学研究，以评估癌前或恶性阶段的Fhit表达。对FHIT抗肿瘤或治疗性导入的临床前研究进行综述，以了解外源性Fhit表达的效果。对于免疫组织化学分析，纳入了26项研究，这些研究分析了至少15例单一类型肿瘤。对于癌前病变，纳入了9项研究，这些研究分析了至少4例。对于FHIT导入的研究，纳入了9项已发表的研究。
使用每项研究的原始数据，我们评估了FHIT癌症治疗的基本原理和潜在贡献。数据由2位作者独立提取，研究质量由另外2位作者评估。
总体而言，60%（1162/1948例）的原发性肿瘤显示癌细胞中Fhit蛋白表达缺失或明显降低。对癌前病变或早期癌症的研究表明，0%至93%的样本中Fhit蛋白表达缺失或明显降低（总体为31%[127/408例]）。使用来自人类肺癌、头颈癌、食管癌、胃癌、宫颈癌、胰腺癌和肾癌的26种癌症衍生细胞系进行的临床前研究表明，在30项细胞系实验中的17项（57%）中，重新导入FHIT导致体外肿瘤细胞生长或体内致瘤性受到抑制。人类预防性癌症治疗的模型系统表明，在某些情况下将病毒载体介导的FHIT经口导入Fhit缺陷小鼠可能预防致癌物诱导的肿瘤发生。
这些发现表明，FHIT基因治疗在临床上可能对癌症治疗以及预防致癌物诱导的肿瘤发生具有潜在作用，这为进一步开展涉及FHIT导入的研究提供了理论依据。
