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Cytotoxic Effects of Topotecan Combined with Various Active G2/M-Phase Anticancer Drugs in Human Tumor-Derived Cell Lines

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Abstract

Topotecan (TPT) is a DNA-Topoisomerase I poison that exhibitsantitumor activity. TPT, like other DNA-damaging agents, arrests ordelays cell cycle progression during S- and G2-phase in a widevariety of tumor-derived cell lines. Particularly, the G2-arrest gives time for the cell to repair its DNA lesions prior tostarting a new cell cycle. Based on these observations, we assessedthe interaction between TPT and G2/M-active agents in p53–mutatedcell lines of diverse origin in order to achieve cell toxicity. Two short-term sequential schedules were administered(TPT → G2/M-active drug at the interval of greatest TPT-inducedG2/M-phase cell arrest, and G2/M-active drug → TPT), in threehuman tumor-derived cell lines with proven sensitivity to the following drugs: Bleomycin in HEp-2 (squamous larynx carcinoma);Docetaxel in SKBr-3 (breast adenocarcinoma); Etoposide in NCI-H23(non-small-cell lung cancer). Our results show that: 1) SequentialTPT → G2/M-active drugs are synergistic when administrationoverlapped the maximum percentage of TPT-induced G2/M–phase cellarrest interval in all three mutated p53 cell lines; 2) the reversesequential schedule (G2/M-active drug → TPT) was antagonistic,and being only additive for Etoposide → TPT association. Inconclusion, our findings further support the potential cytotoxicrole of TPT in combination with other active drugs when the correctschedule of administration is applied. In addition, they provide arationale for new applications in clinical trials using short-termsequential TPT → G2/M-active drugs.

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Authors and Affiliations

  1. Medical Oncology Service, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain

    Miquel Taron, Carmen Plasencia, Albert Abad, Cristina Martin & Mónica Guillot

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  1. Miquel Taron
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Taron, M., Plasencia, C., Abad, A. et al. Cytotoxic Effects of Topotecan Combined with Various Active G2/M-Phase Anticancer Drugs in Human Tumor-Derived Cell Lines. Invest New Drugs 18, 139–148 (2000). https://doi.org/10.1023/A:1006325929424

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