Bunn Paul A
Lung Cancer Program and Department of Medicine, University of Colorado Cancer Center and University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Semin Oncol. 2002 Jun;29(3 Suppl 9):17-22. doi: 10.1053/sonc.2002.34268.
Lung cancer is the leading cause of cancer death in the United States and throughout the world. The overall 5-year survival rate for lung cancer is dismal: 14% in the United States and even lower in other parts of the world. Recent developments in the armamentarium of chemotherapeutic agents for lung cancer have shown that two-drug combinations improve survival, relieve symptoms, and improve quality of life; however, complete response rates are still approximately 1% in stage IV disease and less than 20% of advanced stage patients survive 2 years. Therefore, improved therapeutic agents that increase efficacy are sorely needed. Most lung cancers overexpress thymidylate synthase and a variety of genes involved in cell cycle regulation. Previous studies have shown that some inhibitors of DNA synthesis (eg, gemcitabine) can improve the survival of advanced lung cancer patients, especially when combined with other agents such as cisplatin. The multitargeted antifolate, pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) was developed because it inhibits multiple enzymes involved in DNA synthesis including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase. The early studies of pemetrexed showed that the important dose-limiting toxicities were myelosuppression, mucositis, and diarrhea, all of which are common with any antimetabolite. Subsequent studies described in this article will show that these toxicities can be significantly reduced by the use of vitamin supplementation with folate and B12, and that pemetrexed has considerable activity in non-small cell lung cancer and mesothelioma.
肺癌是美国乃至全球癌症死亡的主要原因。肺癌的总体5年生存率令人沮丧：在美国为14%，在世界其他地区甚至更低。肺癌化疗药物库的最新进展表明，两药联合可提高生存率、缓解症状并改善生活质量；然而，IV期疾病的完全缓解率仍约为1%，晚期患者中不到20%能存活2年。因此，迫切需要能提高疗效的改良治疗药物。大多数肺癌过度表达胸苷酸合成酶以及多种参与细胞周期调控的基因。先前的研究表明，一些DNA合成抑制剂（如吉西他滨）可提高晚期肺癌患者的生存率，尤其是与顺铂等其他药物联合使用时。多靶点抗叶酸药物培美曲塞（力比泰；礼来公司，印第安纳波利斯，印第安纳州）的研发是因为它能抑制多种参与DNA合成的酶，包括胸苷酸合成酶、二氢叶酸还原酶和甘氨酰胺核苷酸甲酰转移酶。培美曲塞的早期研究表明，重要的剂量限制性毒性是骨髓抑制、粘膜炎和腹泻，所有这些都是任何抗代谢药物常见的毒性。本文所述的后续研究将表明，通过补充叶酸和维生素B12可显著降低这些毒性，并且培美曲塞在非小细胞肺癌和间皮瘤中具有相当的活性。
