st-1481 and edotecarin

Topoisomerase I (TopoI), an essential enzyme, produces a DNA single strand break allowing DNA relaxation for replication. The enzymatic mechanism involves sequential transesterifcations. The breakage and closure reactions generate phosphodiester bonds and similar free energies, so the reaction is freely reversible. The TopoI reaction intermediate consists of enzyme covalently linked to DNA dubbed a 'cleavable complex'. Covalently bound TopoI-DNA complexes can be recovered. Camptothecin analogs, topotecan and irinotecan, are approved TopoI-targeted drugs. Both have limitations due to the equilibrium between the camptothecin lactone and ring-opened forms. Several strategies are being explored to develop improved TopoI inhibitors. Homocamptothecins, in which the metabolically labile camptothecin lactone is replaced with a more stable seven-membered beta-hydroxylactone, are potent anticancer agents. Gimatecan is a seven-position modified lipophilic camptothecin developed to provide rapid uptake and accumulation in cells and a stable TopoI-DNA-drug ternary complex. Diflomotecan, a homocamptothecin, and gimatecan are in Phase II clinical trial. Among non-camptothecins, edotecarin, an indolocarbazole that results in DNA C/T-G cleavage compared with T-G/A for camptothecins, is in Phase II clinical trial. Indenoisoquinolines were identified as TopoI inhibitors by the NCI 60-cell line COMPARE analysis. Co-crystal structures of two indenoisoquinolines with TopoI-DNA elucidated the structure of the ternary complex. Indenoisoquinolines are in preclinical development. Dibenzonaphthyridinone TopoI inhibitors have undergone extensive structure-activity examination. ARC-111 was selected for in-depth preclinical study. Biomarkers are under investigation to predict clinical efficacy from preclinical models, to allow determination of drug targeting in vivo and to aid selection of patients most likely to benefit from TopoI inhibitor therapy. gamma-H2AX formation may be a useful pharmacodynamic marker. A gene signature developed for topotecan sensitivity/resistance may have value in patient identification. Convergence of these efforts should result in clinically effective second generation TopoI inhibitors.

Topics: Animals; Antineoplastic Agents; Biomarkers; Camptothecin; Carbazoles; Humans; Indenes; Indoles; Isoquinolines; Naphthyridines; Topoisomerase I Inhibitors

Recent clinical trial results suggest that anti-angiogenic therapy may be effective against recurrent malignant glioma. Though these treatments prolong progression-free survival, the extent to which they prolong overall survival is unknown. We pooled data from 34 patients treated at a single institution on phase II clinical trials of bevacizumab and cediranib, and we compared these data to 18 patients treated on clinical trials of cytotoxic chemotherapies. In univariate and multivariate analyses, treatment group was a significant predictor of progression-free but not overall survival. Median progression-free survival was 8 vs. 22 weeks in patients treated with cytotoxic as compared to anti-angiogenic therapy (P = 0.01). Median overall survival was nearly identical in the two groups (39 vs. 37 weeks). The results of this exploratory analysis suggest that anti-angiogenic therapy may fail to prolong overall survival in patients with recurrent malignant glioma. If this conclusion proves correct, progression-free survival may be an inappropriate endpoint for phase II trials of anti-angiogenic therapies.

Topics: Adult; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Camptothecin; Carbazoles; Clinical Trials as Topic; Disease-Free Survival; Female; Glioma; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Recurrence, Local; Quinazolines; Survival Analysis