title: The modulatory effect of melatonin on genotoxicity of irinotecan in healthy human lymphocytes and cancer cells.
abstract: Drug-target interactions can be modified by adding modulatory agents to increase treatment efficacy and clinical outcome. Combination chemotherapy has become increasingly important because drugs acting synergistically can achieve therapeutic effects at substantially lower doses and with a limited spectrum of side effects. Irinotecan, known as one of the camptothecin analogs, has shown a broad spectrum of antitumor activity against various malignancies. In this study, we evaluated the effect of melatonin on the genotoxic activity of irinotecan in healthy human lymphocytes and a lung cancer cell line (A549) and a colorectal adenocarcinoma cell line (HT29) in vitro. Irinotecan, as a single agent, was shown to induce DNA damage in all types of analyzed cells. The combination of melatonin at concentrations of 50 μM with increasing doses of irinotecan (7.5, 15, 30, and 60 μM) resulted in an increase in the amount of DNA damage in A549 and HT29 cancer cells, but was not effective in inducing DNA damage in healthy human lymphocytes. Analysis of the efficacy of DNA repair, performed after 60 and 120 minutes of postincubation, showed the gradual decrease of DNA percentage in comet tails during repair postincubation in all experimental samples. Our results indicate that melatonin can modulate the genotoxic activity of irinotecan and DNA repair efficacy in human cancer cells in vitro. These findings may be supportive for the optimization of therapeutic efficacy in irinotecan treatment.
authors.affiliation: Laboratory of Cytogenetics, Department of General Genetics, Molecular Biology and Biotechnology, University of Lodz, Lodz, Poland.
authors.forename: Renata
authors.initials: R
authors.lastname: Kontek
authors.forename: Hanna
authors.initials: H
authors.lastname: Nowicka
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D016587:Antimutagenic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy*; D008214:Lymphocytes / Q000187:drug effects*; D008550:Melatonin / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D016587:Antimutagenic Agents; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D008550:Melatonin; D002166:Camptothecin