Oelmann Elisabeth, Haghgu Susan, Kulimova Emma, Mesters Rolf M, Kienast Joachim, Herbst Hermann, Schmitmann Christiane, Kolkmeyer Astrid, Serve Hubert, Berdel Wolfgang E
Department of Medicine, Hematology and Oncology, University Hospital, Westfaelische Wilhelms Universitaet Muenster, Muenster, Germany.
Int J Oncol. 2004 Oct;25(4):1001-12.
RhKGF is developed for prevention and treatment of chemotherapy- and radiation-induced epithelial damage in cancer patients. Little information exists on growth modulation of malignant cells by KGF. We have tested the anchorage-independent clonal growth of 35 human tumor and 22 lymphoma and leukemia cell lines in semisolid media with or without rhKGF. Growth of the majority of cell lines was not significantly influenced by rhKGF. Growth of 5 cell lines (2 lung, 1 stomach, 1 colorectal, 1 breast) was significantly stimulated by rhKGF. The effect was dose-dependent with significant stimulation at concentrations >1-10 ng/ml. Growth modulation was amplified by serum reduction and abolished by anti-hKGF antibodies. Responding cell lines expressed KGF receptor RNA and showed specific KGF-binding. To determine whether KGF-induced higher colony numbers represented cell divisions with resulting differentiation and growth arrest or self-renewal we performed experiments on serial plating efficacy of colony-derived tumor cells with or without continued presence of rhKGF. Results revealed KGF stimulation of colony formation as representing increase of cellular self-renewal. To test possible interaction of rhKGF with activity of cytotoxic drugs in clinical protocols, we have used combination protocols with 5-fluorouracil (5-FU). Results showed that rhKGF incubation before, after (or both) addition of 5-FU did not diminish the sensitivity of tumor cells to 5-FU cytotoxicity under serum concentrations relevant for the clinical situation. In conclusion, some epithelial tumor cells have receptors for KGF signaling for clonal growth. When considered in the planning of treatment protocols, this effect is unlikely to compromise chemotherapy sensitivity.
重组人角质形成细胞生长因子（RhKGF）被开发用于预防和治疗癌症患者化疗和放疗引起的上皮损伤。关于角质形成细胞生长因子（KGF）对恶性细胞生长调节的信息很少。我们检测了35种人类肿瘤细胞系以及22种淋巴瘤和白血病细胞系在添加或不添加重组人角质形成细胞生长因子（rhKGF）的半固体培养基中的非锚定依赖性克隆生长情况。大多数细胞系的生长未受到rhKGF的显著影响。5种细胞系（2种肺癌、1种胃癌、1种结直肠癌、1种乳腺癌）的生长受到rhKGF的显著刺激。这种作用呈剂量依赖性，在浓度>1 - 10 ng/ml时具有显著刺激作用。血清减少可增强生长调节作用，抗人角质形成细胞生长因子（hKGF）抗体可消除该作用。有反应的细胞系表达角质形成细胞生长因子受体RNA并显示出特异性的角质形成细胞生长因子结合。为了确定角质形成细胞生长因子诱导的更高集落数是代表细胞分裂导致分化和生长停滞还是自我更新，我们对有或无rhKGF持续存在情况下集落衍生肿瘤细胞的连续接种效率进行了实验。结果显示，角质形成细胞生长因子刺激集落形成代表细胞自我更新增加。为了测试在临床方案中rhKGF与细胞毒性药物活性可能的相互作用，我们使用了5 - 氟尿嘧啶（5 - FU）联合方案。结果表明，在与临床情况相关的血清浓度下，在添加5 - FU之前、之后（或两者）孵育rhKGF不会降低肿瘤细胞对5 - FU细胞毒性的敏感性。总之，一些上皮肿瘤细胞具有用于克隆生长的角质形成细胞生长因子信号受体。在制定治疗方案时考虑到这一点，这种作用不太可能损害化疗敏感性。
