1st Department of Obstetrics and Gynaecology, Ludwig-Maximilians-University Munich, Maistrasse 11, Munich 80337, Germany.
Arch Gynecol Obstet. 2011 May;283(5):1087-96. doi: 10.1007/s00404-010-1757-x. Epub 2010 Nov 17.
Ovarian cancer is a difficult to treat cancer entity with a high relapse rate. After initial surgery and chemotherapy, only a few options for therapeutic treatment remain in case of cancer recurrence. New treatment options with improved efficacies to circumvent acquired or pre-existing drug resistance are needed.
This survey focuses on new prospective drugs for ovarian cancer treatment that either cause direct damage to the nuclear DNA or inhibit chromosome segregation by acting as mitotic spindle inhibitors.
Among a plethora of currently tested and proposed new drugs for ovarian cancer treatment, only a few appear to meet the criteria of sufficient and reliable efficacy with tolerable toxicity. These include the naturally occurring DNA-alkylating alkaloid trabectedin, the nitrogen mustard prodrug canfosfamide, and the synthetic kinase inhibitor ON-01910. The latter inhibits mitotic spindle formation without a direct tubulin interaction, avoiding adverse neurotoxic reactions common to the taxanes. Further, epothilones and oxaliplatin, already approved drugs for other cancer entities, show promising activity against ovarian cancer; they are even of interest as a first-line treatment option.
Although the current focus and interest of modern cancer drug design tends to be more specific and targeted therapies, including therapeutic antibodies and specific small molecules to inhibit growth-, apoptosis-, and angiogenesis-regulating signalling cascades, the main target for ovarian cancer treatment appears to remain its basic, though uncontrolled working proliferation machinery. This includes the current gold standard for ovarian cancer chemotherapy, carboplatin, and taxanes, as well as the few remaining alternatives, such as topotecan, doxorubicin, and gemcitabine, which all rely on their ability to bind to or to modify the DNA or the chromosome-separating spindle apparatus. Thus, the genomic integrity and replication machinery of ovarian cancer cells prove to represent an established, and obviously still effective target to be tackled for ovarian cancer treatment.
卵巢癌是一种治疗难度大、复发率高的癌症实体。在初始手术和化疗后，如果癌症复发，只有少数治疗选择。需要新的治疗选择，以提高疗效，规避获得性或预先存在的耐药性。
本调查侧重于治疗卵巢癌的新的有前途的药物，这些药物要么直接对核 DNA 造成损害，要么通过作为有丝分裂纺锤体抑制剂来抑制染色体分离。
在目前测试和提出的用于治疗卵巢癌的大量新药中，只有少数药物似乎具有足够和可靠的疗效，同时毒性可耐受。这些药物包括天然存在的 DNA 烷化生物碱 trabectedin、氮芥前体 canfosfamide 以及合成激酶抑制剂 ON-01910。后者通过不直接与微管蛋白相互作用来抑制有丝分裂纺锤体的形成，从而避免了紫杉烷类药物常见的不良神经毒性反应。此外，已经批准用于其他癌症实体的 epothilones 和 oxaliplatin 对卵巢癌也显示出有希望的活性；它们甚至作为一线治疗选择也很有意义。
尽管现代癌症药物设计的当前重点和兴趣往往是更具体和靶向的治疗方法，包括治疗性抗体和特定的小分子来抑制生长、凋亡和血管生成调节信号级联，但卵巢癌治疗的主要目标似乎仍然是其基本的、尽管不受控制的增殖机制。这包括卵巢癌化疗的当前金标准 carboplatin 和紫杉烷，以及少数剩余的替代药物，如 topotecan、多柔比星和吉西他滨，它们都依赖于它们结合或修饰 DNA 或染色体分离纺锤体装置的能力。因此，卵巢癌细胞的基因组完整性和复制机制证明是一个已确立的、显然仍然有效的靶点，可用于治疗卵巢癌。
