The influence of tumour microenvironmental factors on the efficacy of cisplatin and novel platinum(IV) complexes

H. R. Mellor, S. Snelling, M. D. Hall, S. Modok, M. Jaffar, T. W. Hambley, R. Callaghan

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The chemotherapeutic drug cisplatin is an important treatment for many types of solid tumours, in particular non-small cell lung cancer (NSCLC). Platinum(IV) complexes offer several advantages to cisplatin due to their requirement for reduction to the active platinum(II) form to elicit cytotoxicity. This should minimise non-specific effects and facilitate higher amounts of the active complexes reaching the target DNA. Hypoxia and a quiescent cell population are features of the tumour microenvironment known to lead to resistance to many chemotherapeutic agents. It is unclear how these microenvironmental factors will impact on the efficacy of novel platinum(IV) complexes. Consequently, the cytotoxicities of several platinum drugs were determined in monolayer and tumour spheroid cultures derived from NSCLC lines. Platinum(IV) reduction potential correlated well with cytotoxicity. The complex containing a chloro axial ligand demonstrated the greatest potency and the drug with the hydroxy ligand was the least effective. Although drug cytotoxicity was not enhanced under hypoxic conditions, both cisplatin and the platinum(IV) complexes retained full potency. In addition, all of the platinum drugs retained the ability to evoke apoptosis in quiescent cells. In summary, unlike many anticancer drugs, the platinum(IV) complexes retain cytotoxic potency under resistance-inducing tumour microenvironmental conditions and warrant further investigation as more selective alternatives to current platinum-based therapy for the treatment of solid tumours. © 2005 Elsevier Inc. All rights reserved.
    Original languageEnglish
    Pages (from-to)1137-1146
    Number of pages9
    JournalBiochemical Pharmacology
    Volume70
    Issue number8
    DOIs
    Publication statusPublished - 15 Oct 2005

    Keywords

    • Cisplatin
    • Hypoxia
    • Platinum(IV)
    • Quiescent cells
    • Solid tumour models
    • Tumour microenvironment

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