APOPTOTIC CELL DEATH OF MALINGANT GLIOMA INDUCED BY HYPERTHERMIA : THE BASIC MECHANISMS AND CLINICAL APPLICATION

热疗是治疗恶性胶质瘤的有效方法之一。世界上正在进行许多临床试验。然而，其抗肿瘤机制的细节仍未得到很好的解决。我们已经报道了172个胶质瘤细胞在热休克刺激下发生了G1期停滞和凋亡细胞死亡。同时诱导细胞凋亡相关因子Bax、Bax和P53蛋白的表达。这些现象与细胞周期密切相关。细胞周期蛋白依赖性激酶抑制因子(CKIs)之一p21被同时激活(Fuse T et al，Biochem BiPhys Commun，1996)。已有报道P53直接调控p21。我们发现具有突变型P53基因的T98G胶质瘤细胞在热休克过程中发生了细胞凋亡。P21的激活不伴随P53的诱导。我们的数据表明，除了P53相关的信号转导外，还有另一条信号通路通向CKI(Fuse T et al，NeuroSurgery 1998)。恶性胶质瘤对许多抗肿瘤药物表现出耐药性。前列腺素A1系列(PGA1系列)在体内和体外对多种肿瘤具有抗增殖活性，在恶性肿瘤的化疗中具有潜在的应用前景。我们发现PGA1抑制了A172胶质瘤细胞的生长并导致G1期停滞。PGA1诱导p21mRNA和蛋白表达。另一方面，细胞周期蛋白E依赖的激酶活性明显降低。PGA1似乎通过两种不同的途径抑制肿瘤细胞的生长：诱导p21和抑制细胞周期蛋白E(Tanikawa M等人，J Biol Chem 1998)。尽管其分子和细胞机制尚不清楚，但p21在胶质瘤细胞的生长调节和治疗策略中发挥着重要作用。热疗和前列环素在脑胶质瘤的治疗中具有潜在的应用价值。

Hyperthermia is one of the effective therapeutic methods for malignant glioma. Many clinical trials are going on in the world. However, the details of anti-tumor mechanism haven't been well resolved. We already reported A172 glioma cells underwent G1 arrest and apoptotic cell death by heat shock stimulation. In the meantime, apoptosis related factors such as bax mRNA, Bax and p53 protein were induced. These phenomena had close relation with cell cycle. One of the cyclin dependent kinase inhibitors (CKIs), p21, was activated simultaneously (Fuse T et al, Biochem Biophys Res Commun, 1996). P53 has been reported to regulate p21 directly. We showed T98G glioma cells, which had mutant type p53, suffered apoptotic cell death by heat shock. The activation of p21 was not accompanied by p53 induction. Our data means there is alternative signal pathway to CKIs besides p53 related transduction (Fuse T et al, Neurosurgery 1998).Malignant gliomas manifest resistance against many anti-tumor drugs. Prostaglandin A1 series (PGA1s) have anti-proliferative activity for many cancers in vivo and in vitro, and PGA1s are potentially useful in chemotherapy of malignant tumors. We showed PGA1 inhibited cell growth and caused G1 arrest in A172 glioma cells. PGA1 induced the expression of p21 mRNA and protein. On the other hand, cycline E dependent kinase activity was markedly reduced. PGA1 seem to inhibit tumor cell growth through two distinct pathways : the induction of p21 and the suppression of cyclin E (Tanikawa M et al, J Biol Chem 1998).Although the molecular and cellular mechanisms remain elusive, p21 plays an important role in growth regulation of glioma cells and therapeutic strategy. Hyperthermia and PGA1 would be potentially useful in glioma therapy.