ArticleCancer chemotherapy and pharmacology2016
Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors.
Article in Cancer chemotherapy and pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Targeting DNA Topoisomerase I for the Treatment of Cancer: Past, Present and Future.Journal of molecular biology · 2026Review
- New Approaches to Investigate Novel Agents in Ewing Sarcoma: A Report From the Children's Oncology Group Bone Tumor Committee.Pediatric blood & cancer · 2025Review
- Multidrug Resistance: Are We Still Afraid of the Big Bad Wolf.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Phase 1 studies of the indenoisoquinolines LMP776 and LMP744 in patients with solid tumors and lymphomas.Cancer chemotherapy and pharmacology · 2025Article
- Mechanisms of telomere maintenance and associated therapeutic vulnerabilities in malignant gliomas.Neuro-oncology · 2024Review
- Treatment with novel topoisomerase inhibitors in Ewing sarcoma models reveals heterogeneity of tumor response.Frontiers in cell and developmental biology · 2024Article
- Evaluating the indotecan-neutropenia relationship in patients with solid tumors by population pharmacokinetic modeling and sigmoidal ECancer chemotherapy and pharmacology · 2023Article
- Payload diversification: a key step in the development of antibody-drug conjugates.Journal of hematology & oncology · 2023Review
- Article
- DNA topoisomerases as molecular targets for anticancer drugs.Journal of enzyme inhibition and medicinal chemistry · 2020Review
- The Indenoisoquinoline LMP517: A Novel Antitumor Agent Targeting both TOP1 and TOP2.Molecular cancer therapeutics · 2020Article
- BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers.Science translational medicine · 2020Article
- The Indenoisoquinoline TOP1 Inhibitors Selectively Target Homologous Recombination-Deficient and Schlafen 11-Positive Cancer Cells and Synergize with Olaparib.Clinical cancer research : an official journal of the American Association for Cancer Research · 2019Article
- Schlafen 11 (SLFN11), a restriction factor for replicative stress induced by DNA-targeting anti-cancer therapies.Pharmacology & therapeutics · 2019Review
- Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize theJournal of the American Chemical Society · 2019Article
- A review of the molecular design and biological activities of RXR agonists.Medicinal research reviews · 2019Review
- NCI Comparative Oncology Program Testing of Non-Camptothecin Indenoisoquinoline Topoisomerase I Inhibitors in Naturally Occurring Canine Lymphoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2018Article
- Recent developments in topoisomerase-targeted cancer chemotherapy.Acta pharmaceutica Sinica. B · 2018Review
- Novel Fluoroindenoisoquinoline Non-Camptothecin Topoisomerase I Inhibitors.Molecular cancer therapeutics · 2018Article
- Topoisomerases as anticancer targets.The Biochemical journal · 2018Review
Corrections and comments
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Authors and funding
22 authors.
Funding
Abstract
purposeIndenoisoquinolines are non-camptothecin topoisomerase I (TopI) inhibitors that overcome the limitations of camptothecins: chemical instability and camptothecin resistance. Two dosing schedules of the novel indenoisoquinoline, indotecan (LMP400), were evaluated in patients with advanced solid tumors.
methodsThe maximum tolerated dose (MTD), toxicities, and pharmacokinetics of two indotecan drug administration schedules (daily for 5 days or weekly) were investigated. Modulation of TopI and the phosphorylation of histone H2AX (γH2AX) were assayed in tumor biopsies; γH2AX levels were also evaluated in circulating tumor cells (CTCs) and hair follicles to assess DNA damage response.
resultsAn MTD of 60 mg/m(2)/day was established for the daily regimen, compared to 90 mg/m(2) for the weekly regimen. The TopI response to drug showed target engagement in a subset of tumor biopsies. Pharmacokinetics profiles demonstrated a prolonged terminal half-life and tissue accumulation compared to topotecan. Dose-dependent decreases in total CTCs were measured in seven patients. Formation of γH2AX-positive foci in CTCs (day 3) and hair follicles (4-6 h) was observed following treatment.
conclusionsWe established the MTD of two dosing schedules for a novel TopI inhibitor, indotecan. Target engagement was demonstrated as Top1 downregulation and γH2AX response. No objective responses were observed on either schedule in this small patient cohort. The principal toxicity of both schedules was myelosuppression; no significant gastrointestinal problems were observed. Increased DNA damage response was observed in CTCs, hair follicles, and a subset of tumor biopsies.
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