New emerging drugs targeting the genomic integrity and replication machinery in ovarian cancer.

Arch Gynecol Obstet. 2010 Nov 17

Brüning A, Mylonas I.

1st Department of Obstetrics and Gynaecology, Ludwig-Maximilians-University Munich, Maistrasse 11, Munich, 80337, Germany.

Abstract
INTRODUCTION: 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.

MATERIALS: 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.

RESULTS: 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 Yondelis, 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.

DISCUSSION: 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.

PMID: 21082186

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