st-1481 and Colonic-Neoplasms

The lipophilic, orally bioavailable camptothecin analogue gimatecan is characterized by improved efficacy over conventional camptothecins on human tumor xenografts. Gimatecan produced excellent outcomes orally with prolonged, low-dose, daily treatments. The aim of this study was to assess the antitumor efficacy of i.v. administered gimatecan.. The antitumor activity of gimatecan delivered i.v. q4dx4 was evaluated in nude mice bearing human tumors and compared to clinically available anticancer drugs.. Intravenous administration of gimatecan showed superior efficacy with remarkable achievements at well tolerated doses. Moreover, prolonged treatments with i.v. administered gimatecan showed efficacy in models of cancer refractory to current therapeutic approaches, like an orthotopic brain tumor.. Although the oral route is practical for gimatecan administration, the results support the interest in developing a suitable i.v. formulation in an attempt to further exploit the therapeutic potential of the compound.

Topics: Administration, Oral; Animals; Apoptosis; Astrocytoma; Bone Neoplasms; Camptothecin; Cell Proliferation; Colonic Neoplasms; Female; Humans; Mice; Mice, Nude; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

We previously reported that the G-quadruplex (G4) ligand RHPS4 potentiates the antitumor activity of camptothecins both in vitro and in tumor xenografts. The present study aims at investigating the mechanisms involved in this specific drug interaction.. Combination index test was used to evaluate the interaction between G4 ligands and standard or novel Topo I inhibitors. Chromatin immunoprecipitation was performed to study the presence at telomeres of various types of topisomerase, while immunolabeling experiments were performed to measure the activation of DNA damage both in vitro and in tumor xenografts.. We report that integration of the Topo I inhibitor SN-38, but not the Topo II poison doxorubicin with telomere-based therapy is strongly effective and the sequence of drug administration is critical in determining the synergistic interaction, impairing the cell ability to recover from drug-induced cytotoxicity. The synergistic effect of this combination was also observed by using novel camptothecins and, more interestingly, mice treated with ST1481/RHPS4 combination showed an inhibition and delay of tumor growth as well as an increased survival. The study of the mechanism(s) revealed that treatment with G4 ligands increased Topo I at the telomeres and the functional relevance of this observation was directly assessed by showing that standard and novel camptothecins stabilized DNA damage both in vitro and in xenografts.. Our results demonstrate an outstanding efficacy of Topo I inhibitors/G4 ligands combination, which likely reflects an enhanced and persistent activation of DNA damage response as a critical determinant of the therapeutic improvement.

Topics: Acridines; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Camptothecin; Cell Cycle; Cell Survival; Cells, Cultured; Colonic Neoplasms; DNA Damage; Drug Synergism; G-Quadruplexes; HCT116 Cells; HT29 Cells; Humans; Irinotecan; Male; Mice; Mice, Nude; Telomere; Topoisomerase I Inhibitors; Treatment Outcome; Xenograft Model Antitumor Assays