Novel Stable Camptothecin Derivatives Replacing the E-Ring Lactone by a Ketone Function Are Potent Inhibitors of Topoisomerase I and Promising Antitumor Drugs

Abstract

The E-ring lactone is the Achilles' heel of camptothecin derivatives: although it is considered necessary for the inhibition of the enzyme topoisomerase I (topo1), the opening of the lactone into a carboxylate abolishes the generation of topo1-mediated DNA breaks. S38809 is a novel camptothecin analog with a stable 5-membered E-ring ketone; therefore, it lacks the lactone function. DNA relaxation and cleavage assays revealed that S38809 functions as a typical topo1 poison by stimulating DNA cleavage at T2G sites. The activity was strongly dependent on the stereochemistry of the C-7 carbon atom that bears the hydroxy group. S38809 proved to be a potent cytotoxic agent, with a mean IC 50 of 5.4 nM versus 11.6 nM for topotecan and 3.3 nM for SN38 (the active metabolite of irinotecan) on a panel of 31 human tumor cell lines. The cytotoxicity of S38809 and its ability to stabilize cleavable complexes was considerably reduced in camptothecin-resistant cells that express a mutated topo1, confirming that topo1 is its primary target. Cell death induced by topo1 poisoning requires the conversion of DNA single-strand breaks into double-strand breaks that can be detected by the formation of phosphorylated histone H2AX. In HCT116 cells, topotecan, SN38, and S38809 induced histone H2AX phosphorylation in S phase of the cell cycle, with S38809 being as potent as SN38 and 5-fold more potent than topotecan. In vivo, S38809 showed a marked antitumor activity against HCT116 xenografts. These findings open a new route for improving the pharmacological properties of camptothecin derivatives.

Organic Anion-Transporting Polypeptide 1B1 Mediates Transport of Gimatecan and BNP1350 and Can Be Inhibited by Several Classic ATP-Binding Cassette (ABC) B1 and/or ABCG2 Inhibitors

“…This has led to the development of seven-position modified lipophilic CPT derivatives (e.g., gimatecan and BNP1350) (Huang et al, 2007) and stable five-membered E-ring ketone CPTs (Lansiaux et al, 2007). In the present study, we show that gimatecan and BNP1350 are both transported by human OATP1B1.…”

Identification of DNA Repair Pathways That Affect the Survival of Ovarian Cancer Cells Treated with a Poly(ADP-Ribose) Polymerase Inhibitor in a Novel Drug Combination

“…For clonogenic assays, percentage survival at each drug concentration was normalized to the vehicletreated control for the given siRNA. For phospho-H2AX analysis, cells were stained as described but with 2 g/ml anti-phospho-H2AX antibody (Lansiaux et al, 2007). Cells were exposed to ionizing and ultraviolet radiation using a RS-2000 Biological Irradiator (Rad Source, Suwanee, GA) and a UVC-515 Ultraviolet Multilinker (Ultra-Lum, Carson, CA), respectively, 4 to 6 h after cell plating.…”

Evaluation of the cytotoxic effect of camptothecin solid lipid nanoparticles on MCF7 cells

“…These pharmacological properties of CPT result in rapid deactivation and fast clearance from the circulation after it is intravenously administered (Tong & Cheng, 2010). To overcome these drawbacks, CPT analogs and prodrugs have been developed (Lansiaux et al, 2007). For instance, the Food and Drug Administration of the United States of America (FDA) has approved two water soluble derivatives of CPT, topotecan (Hycamptin) and irinotecan (Camptosar), for treating stomach, colon, head, neck, bladder, colorectal and ovarian cancer.…”