Minna J D, Battey J F, Birrer M, Brooks B J, Cuttitta F, DeGreve J, Gazdar A F, Johnson B E, Nau M M, Sausville E A
NCI-Navy Medical Oncology Branch, National Cancer Institute and Naval Hospital, Bethesda, Maryland 20814.
Princess Takamatsu Symp. 1986;17:109-22.
Molecular and cell biologic studies of a large number of lung cancer cell lines of all histologic types have revealed several mechanisms active in the pathogenesis of these cells. Small cell lung cancer (also called "oat cell" lung cancer) has a deletion involving chromosome region 3p(14-23) that is confirmed by DNA restriction fragment length polymorphisms analysis (studies done in collaboration with Dr. Susan Naylor). Several lung cancers of both small cell and non-small cell type (including adeno- and squamous cell lung cancer) express the proto-oncogenes c-, N-, or L-myc, and in some cases more than one of these family members. N-myc appears restricted in its expression to the small cell lung cancer type while c-myc and L-myc can be expressed in both small cell and non-small cell lung cancers. Many lung cancers of all histologic types also express large amounts of p53, which are not correlated with the amount or type of myc gene product expressed. In small cell lung cancer, high levels of myc gene expression are usually associated with gene amplification, and not uncommonly there is rearrangement of some of the amplified copies. In non-small cell lung cancer, expression without amplification or rearrangement of myc genes is seen. In contrast, high level expression of p53 is not associated with gene amplification in any lung cancer type. In addition, to these proto-oncogenes acting at a presumed nuclear locus, there is increased expression of various ras family members and the c-raf-1 proto-oncogene (in collaboration with Dr. Ulf Rapp). Lung cancer cells in tissue culture can grow in medium without serum and few or no other growth factors added. Thus, it appears that lung cancer cells can produce their own growth factors which can act in an "autocrine" fashion. The best characterized example of this is gastrin releasing peptide (GRP, also called bombesin) produced by small cell lung cancer. In at least some small cell lung cancers, interference with GRP action by specific monoclonal antibodies results in inhibition of tumor cell growth in culture and in nude mouse xenografts. Thus, constitutively expressed GRP gene may function as a cellular oncogene under certain circumstances in small cell lung cancer. Based on these observations we are proposing to test monoclonal anti-GRP antibodies in patients.
对大量各种组织学类型的肺癌细胞系进行的分子和细胞生物学研究揭示了这些细胞发病机制中起作用的几种机制。小细胞肺癌（也称为“燕麦细胞”肺癌）存在涉及染色体区域3p(14 - 23)的缺失，这已通过DNA限制性片段长度多态性分析得到证实（与苏珊·内勒博士合作开展的研究）。小细胞和非小细胞类型的几种肺癌（包括腺癌和鳞状细胞肺癌）都表达原癌基因c-、N-或L-myc，在某些情况下，这些家族成员中的不止一种会表达。N-myc的表达似乎仅限于小细胞肺癌类型，而c-myc和L-myc在小细胞和非小细胞肺癌中都可表达。所有组织学类型的许多肺癌也大量表达p53，这与所表达的myc基因产物的数量或类型无关。在小细胞肺癌中，高水平的myc基因表达通常与基因扩增相关，并且扩增的拷贝中常有一些发生重排。在非小细胞肺癌中，可见myc基因无扩增或重排的表达。相比之下，p53的高水平表达在任何肺癌类型中都与基因扩增无关。此外，除了这些作用于假定核位点的原癌基因外，各种ras家族成员和c-raf-1原癌基因的表达也增加了（与乌尔夫·拉普博士合作）。组织培养中的肺癌细胞可以在不添加血清以及很少或不添加其他生长因子的培养基中生长。因此，似乎肺癌细胞可以产生自身的生长因子，这些因子可以以“自分泌”方式发挥作用。对此最具特征的例子是小细胞肺癌产生的胃泌素释放肽（GRP，也称为蛙皮素）。在至少一些小细胞肺癌中，用特异性单克隆抗体干扰GRP的作用会导致培养物中肿瘤细胞生长以及裸鼠异种移植瘤生长受到抑制。因此，在某些情况下，组成性表达的GRP基因可能在小细胞肺癌中作为细胞癌基因发挥作用。基于这些观察结果，我们提议在患者中测试单克隆抗GRP抗体。
