Topotecan Hydrochloride is the water-soluble hydrochloride salt preparation of Topotecan, a potent inhibitor of topoisomerase 1, and an apoptosis inducer, producing proapoptotic and antiproliferative effects. Topotecan is a semisynthetic derivative of the natural product alkaloid camptothecin. It is described to stabilize topoisomerase I/DNA cleavable complexes and promote rapid apoptotic cell death in radiation-resistant human B-lineage acute lymphoblastic leukemia cells.
CAT No: 10-101-124
CAS No:123948-87-8 (net), 119413-54-6 (hydrochloride)
Synonyms/Alias:TPT; SKF-104864A; SKFS-104864-A; 9-[(Dimethylamino)methyl]-10-hydroxy-(20S)-camptothecin · HCl; (S)-10-Dimethylaminomethyl-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2b]quinoline-3,14(4H,12H)-dione · HCl; (20S)-10-Dimethylaminomethyl-4-ethyl
Topotecan Hydrochloride is a semi-synthetic derivative of camptothecin, recognized for its role as a potent inhibitor of DNA topoisomerase I. This compound is highly valued in biochemical and pharmacological research due to its ability to interfere with DNA replication and transcription processes, making it a critical tool in the study of cellular responses to DNA damage. As a water-soluble hydrochloride salt, it offers excellent stability and ease of handling, which supports its widespread application in both in vitro and in vivo experimental models. Researchers appreciate its specificity in targeting topoisomerase I, enabling precise investigation into the mechanisms of DNA strand breakage and repair. The compound's versatility extends to a range of molecular and cellular biology studies, where it serves as a reference agent for evaluating DNA damage response pathways and the efficacy of novel therapeutic strategies.
Cancer Research Models: Topotecan Hydrochloride is extensively utilized in preclinical cancer research to investigate the molecular mechanisms underlying tumor cell sensitivity and resistance to topoisomerase I inhibition. By inducing DNA single-strand breaks, it facilitates the study of apoptosis, cell cycle arrest, and DNA repair pathways in a variety of cancer cell lines. This application is crucial for delineating the cellular factors that influence drug responsiveness and for identifying potential biomarkers predictive of therapeutic outcome. Its use in xenograft and syngeneic mouse models further aids in evaluating tumor growth inhibition and the pharmacodynamics of combination therapies, providing valuable insights into the optimization of anti-cancer regimens.
DNA Damage and Repair Studies: As a specific topoisomerase I inhibitor, Topotecan Hydrochloride is an indispensable reagent for dissecting the molecular events associated with DNA damage and repair. It is commonly employed to induce controlled DNA lesions, enabling researchers to monitor the recruitment and activation of DNA repair proteins, checkpoint kinases, and other components of the DNA damage response machinery. These studies are fundamental to understanding the maintenance of genomic stability and the development of strategies to sensitize cells to genotoxic stress. The compound's ability to generate DNA breaks in a dose- and time-dependent manner makes it ideal for quantitative analyses of repair kinetics and pathway choice.
Pharmacology and Drug Screening: In the context of pharmacological research, Topotecan Hydrochloride serves as a reference standard in high-throughput screening assays designed to identify novel modulators of topoisomerase I activity or agents that synergize with topoisomerase I inhibitors. Its well-characterized mechanism of action allows for the establishment of robust assay systems to evaluate the potency, selectivity, and cytotoxicity of candidate compounds. Moreover, structure-activity relationship studies benefit from its use as a benchmark, facilitating the rational design of next-generation topoisomerase inhibitors with improved efficacy or reduced toxicity.
Cell Cycle Regulation Research: Topotecan Hydrochloride is frequently employed in studies focused on cell cycle dynamics and checkpoint control. By stalling replication forks and activating DNA damage checkpoints, it enables detailed examination of the signaling pathways governing cell cycle progression, arrest, and recovery. Researchers utilize it to probe the role of key regulatory proteins, such as cyclins, CDKs, and checkpoint kinases, in mediating cellular responses to replication stress. These investigations contribute to a deeper understanding of cell cycle regulation under physiological and pathological conditions, informing the development of targeted interventions for diseases characterized by aberrant cell proliferation.
Synthetic Lethality and Combination Therapy Studies: Topotecan Hydrochloride is a valuable tool in exploring synthetic lethality and the potential of combination therapies in oncology research. By selectively inhibiting topoisomerase I, it can be paired with agents targeting complementary DNA repair pathways or cell survival mechanisms, thereby enhancing cytotoxic effects in tumor cells deficient in specific repair functions. This approach is instrumental in identifying effective drug combinations and elucidating mechanisms of resistance, paving the way for more personalized and effective therapeutic strategies.
Genotoxicity and Mechanistic Toxicology: In mechanistic toxicology, Topotecan Hydrochloride is used to induce DNA damage in order to assess cellular responses, genotoxic potential, and the activation of stress response pathways. Its application in genotoxicity assays helps researchers evaluate the impact of DNA strand breaks on cell viability, mutagenesis, and chromosomal stability. These studies are essential for understanding the broader implications of topoisomerase inhibition and for guiding the safe development of new chemical entities with reduced genotoxic liabilities.
The stability and compatibility of topotecan hydrochloride with common infusion solutions and containers were studied. During this study, the leaching of diethylhexyl phthalate (DEHP), a major plasticizer of some polyvinyl chloride (PVC) materials was also investigated. A formulation of topotecan hydrochloride was added to 50 ml PVC infusion bags, polyolefin infusion bags and 150 ml glass bottles containing either 5% dextrose injection or 0.9% sodium chloride injection at an initial nominal topotecan concentration of 0.05 mg ml-1. Additionally, the topotecan hydrochloride formulation was added to 50 ml PVC infusion bags containing either 5% dextrose injection or 0.9% sodium chloride injection at an initial nominal topotecan concentration of 0.025 mg ml-1.
Craig, S. B., Bhatt, U. H., & Patel, K. (1997). Stability and compatibility of topotecan hydrochloride for injection with common infusion solutions and containers. Journal of pharmaceutical and biomedical analysis, 16(2), 199-205.
Ovarian cancer is the most common gynaecological cancer, with an annual incidence of 21.9 per 100,000 women in England and 26.7 per 100,000 in Wales (2000 figures). The prognosis is generally poor, owing to the advanced stage of disease at detection in most cases, and the UK 5-year survival rate is only around 30%. The current guidance issued by the National Institute for Health and Clinical Excellence is that first-line chemotherapy should include either paclitaxel in combination with a platinum-based chemotherapy regimen, or a platinum-based regimen alone (carboplatin or cisplatin). As the majority of patients ultimately relapse and require treatment with second-line therapy, the guidance is that patients who have received recommended first-line therapy should not be treated with the same agents. Pegylated liposomal doxorubicin hydrocholoride (PLDH), topotecan and paclitaxel may therefore be considered alongside other drugs licensed for second-line therapy in advanced ovarian cancer. Participants who had not received paclitaxel as a component of first-line therapy may receive it as second-line.
Main, C., Bojke, L., Griffin, S., Norman, G., Barbieri, M., Mather, L., ... & Riemsma, R. (2006). Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for second-line or subsequent treatment of advanced ovarian cancer: a systematic review and economic evaluation.
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