APOPTOSIS IN ORAL CANCER

口腔癌仍然是癌症死亡的主要原因。五年 口腔癌患者的生存率低于50%; 生存率显著低于许多其他癌症，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 复发性肿瘤的耐药性。该提案旨在解决是否 改变肿瘤细胞接受程序性 细胞死亡（凋亡）有助于发病机制或 口腔或咽部癌复发。特别是， bcl-2家族成员在调节程序化细胞中的作用 口腔/咽癌以及正常口腔组织中的死亡 将检查上皮和癌前病变。成员的bcl- 2基因家族对细胞凋亡既有正调控作用，也有负调控作用。 对各种生理和药理刺激的反应。 bcl-2家族的表达将进一步研究 在正常粘膜中，bcl-2、bcl-xL、bcl-xS、bax、bad和bak的表达与正常粘膜中的bcl-2、bcl-xL、bcl-xS、bax、bad和bak的表达相同。 以及病变的活检标本，包括白斑病和鳞状 细胞癌bcl-2基因在肿瘤细胞存活和分化中的作用 已建立细胞系的化疗/放疗敏感性 也将研究来自口腔或咽癌的肿瘤。超过 30株口腔鳞状细胞癌细胞系 具有已知临床病史的患者的口腔或咽部， 确立了习这些细胞系中有相当数量的细胞显示辐射 尽管存在野生型p53基因，灵敏度 这些已建立的细胞系进行细胞凋亡， 各种各样的刺激，包括化疗和放疗， 并与bcl-2家族成员的表达相关。 如果可以在单个成员的表达之间建立关联， 在bcl-2家族中，将努力确定该基因是否 对于体外存活和/或化疗/放疗是重要的 通过操纵基因的表达， 反义寡核苷酸或腺病毒递送的反式显性 抑制剂的此外，将确定是否增长 作用于口腔上皮细胞的因子将调节 这些细胞存活基因。最后，在体内尝试确定 如果对凋亡的抵抗可能有助于口腔或口腔粘膜的发病机制， 咽部恶性肿瘤，已经产生了转基因动物， 在他们的口腔粘膜中过度表达细胞存活基因bcl-xL。这些 将检查动物是否发生口腔癌， 自发地，或在繁殖到另外的转基因小鼠时， 过度表达上皮生长因子如TGF-α。此外，本发明还提供了一种方法， 这些动物将被检查它们在体内产生肿瘤的能力。 对经典引发剂如苯并蒽的反应。一起 这些研究应该有助于确定是否抑制细胞凋亡 在口腔的发展中起主要或次要的作用 carcinoma.这些研究应该有助于确定是否特定 操纵细胞存活基因的表达-将是一个有用的 增加口腔/咽癌敏感性的辅助治疗 放疗和/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.