APOPTOSIS IN ORAL CANCER

口腔癌仍然是癌症死亡的主要原因。五年 确诊为口腔癌的患者存活率低于50%；a 存活率明显低于许多其他癌症，包括 乳腺癌、结肠癌和肾癌。治疗的一个主要原因 失败是放射和/或化疗的发展 复发肿瘤中的耐药性。这项提案旨在解决是否 肿瘤细胞对程序化反应敏感性的改变 细胞死亡(细胞凋亡)在发病机制或 口腔或咽部癌复发。特别是， Bcl2家族成员在调节程序化细胞中的作用 口腔/咽癌和正常口腔的死亡 上皮组织和癌前病变将被检查。BCL的成员- 2基因家族可正向和负向调节细胞凋亡。 对各种生理和药理刺激的反应。 将对bcl2家族的表达进行分析 BCL-2、BCL-XL、BCL-XS、BAX、BAD、BAK在正常粘膜中的表达 以及病变的活检标本，包括白斑和鳞状细胞 细胞癌。Bc1-2基因在调控肿瘤存活和转移中的作用 已建立的细胞系的化疗/放射治疗敏感性 口腔或咽癌的风险也将被研究。完毕 30株口腔来源的早期传代鳞癌细胞系 有已知临床病史的患者的空洞或咽部 已经成立了。这些细胞系中有相当一部分显示出辐射。 尽管存在野生型p53基因，但仍具有耐药性。敏感度 在这些已建立的细胞系中，有哪些细胞会因 包括化疗和放射在内的各种刺激措施将被 观察bc1-2家族成员的表达情况，并进行相关性分析。 如果可以在单个成员表达之间建立关联 在bcl2家族中，将努力确定该基因是否 对体外存活和/或化疗/放射治疗很重要 通过使用以下两种方法中的一种来控制基因的表达 反义寡核苷酸或腺病毒传递的易显性 抑制剂。此外，还将确定增长是否 作用于口腔上皮细胞的因子将调节其表达 这些细胞生存基因。最后，在体内尝试确定 如果对细胞凋亡的抵抗可以导致口腔溃疡的发生 咽部恶性肿瘤，转基因动物已经产生了 在口腔粘膜中过表达细胞生存基因bclxl。这些 动物也将接受口腔癌的检查。 自发地，或在繁殖到更多的转基因小鼠后 过度表达上皮生长因子，如转化生长因子-α。此外, 这些动物将接受检查，以确定它们是否有能力在 对经典引发剂如苯并菲的反应。同舟共济 这些研究应该有助于确定抑制细胞凋亡 在口腔发育过程中起主要或次要作用 癌症。这些研究应该有助于确定特定的 操纵细胞生存基因的表达-将是一种有用的 辅助治疗提高口腔/咽癌的敏感性 放射和/或化疗。

Oral cancer remains a major cause of cancer mortality. The five year survival rate in patients diagnosed with oral cancer is under 50%; a survival rate that is significantly below many other carcinomas including breast, colon, and renal carcinomas. One major reason for treatment failure is the development of radiation and/or chemotherapeutic resistance in recurrent tumors. This proposal seeks to address whether alterations in the susceptibility of tumor cells to undergo programmed cell death (apoptosis) contributes to either the pathogenesis or recurrence of carcinomas in the oral cavity or pharynx. In particular, the role of members of the bcl-2 family in regulating programmed cell death in carcinomas of the oral cavity/pharynx as well as in normal oral epithelium and premalignant lesions will be examined. Members of the bcl- 2 gene family can both positively and negatively regulate apoptosis in response to a wide variety of physiologic and pharmacologic stimuli. Studies will be undertaken to analyze the expression of bcl-2 family members, bcl-2, bcl-xL, bcl-xS, bax, bad, and bak in normal mucosa as well as biopsy specimens of lesions including leukoplakia and squamous cell carcinoma. The role of bcl-2 genes in regulating the survival and chemotherapeutic/ radio-therapeutic sensitivity of established cell lines from carcinomas of the oral cavity or pharynx will also be studied. Over 30 early passage squamous cell carcinoma cell lines derived from the oral cavity or pharynx of patients with known clinical histories have been established. A significant number of these cell lines display radiation resistance despite the presence of a wild-type p53 gene. The sensitivity of these established cell lines to undergo apoptosis in response to a wide variety of stimuli including chemotherapy and radiation will be investigated and correlated with the expression of bcl-2 family members. If an association can be made between expression of an individual member of the bcl-2 family, efforts will be made to determine whether the gene is important for the in vitro survival and/or chemo/radiotherapy sensitivity by manipulating the expression of the genes using either antisense oligonucleotides or adenoviral-delivered transdominant inhibitors. In addition, determinations will be made as to whether growth factors that act on oral epithelial cells will modulate the expression of these cell survival genes. Finally, in an in vivo attempt to determine if resistance to apoptosis can contribute to the pathogenesis of oral or pharyngeal malignancies, transgenic animals have been produced which overexpress the cell survival gene bcl-xL in their oral mucosa. These animals will be examined for their development of oral cancer either spontaneously, or upon breeding to additional transgenic mice that overexpress epithelial growth factors such as TGF-alpha. In addition, these animals will be examined for their ability to develop tumors in response to classical initiating agents like benzanthracene. Together these studies should help to determine whether inhibition of apoptosis can play either a primary or secondary role in the development of oral carcinoma. These studies should help to determine whether specific manipulation of the expression of cell survival genes-will be a useful adjunct therapy to increase the sensitivity of oral/pharyngeal carcinomas to radiation and/or chemotherapy.