Inhibition of homologous recombination repair with Pentoxifylline targets G2 cells generated by radiotherapy and induces major enhancements of the toxicity of cisplatin and melphalan given after irradiation - PubMed (original) (raw)

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Inhibition of homologous recombination repair with Pentoxifylline targets G2 cells generated by radiotherapy and induces major enhancements of the toxicity of cisplatin and melphalan given after irradiation

Lothar Bohm. Radiat Oncol. 2006.

Abstract

The presentation reviews the modus operandi of the dose modifying drug Pentoxifylline and the dose enhancement factors which can be achieved in different cell types. Preclinical and clinical data show that Pentoxifylline improves the oxygenation of hypoxic tumours and enhances tumour control by irradiation. In vitro experiments demonstrate that Pentoxifylline also operates when oxygen is not limiting and produces dose modifying factors in the region of 1.2-2.0. This oxygen independent effect is poorly understood. In p53 mutant cells irradiation induces a G2 block which is abrogated by Pentoxifylline. The enhancement of cell kill observed when Pentoxifylline and irradiation are given together could arise from rapid entry of damaged tumour cells into mitosis and propagation of DNA lesions as the result of curtailment of repair time. Recovery ratios and repair experiments using CFGE after high dose irradiation demonstrate that Pentoxifylline inhibits repair directly and that curtailment of repair time is not the explanation. Use of the repair defective xrs1 and the parental repair competent CHO-K1 cell line shows that Pentoxifylline inhibits homologous recombination repair which operates predominantly in the G2 phase of the cell cycle. When irradiated cells residing in G2 phase are exposed to very low doses of cisplatin at a toxic dose of 5%. (TC: 0.05) massive toxicity enhancements up to a factor of 80 are observed in melanoma, squamous carcinoma and prostate tumour cell lines. Enhancements of radiotoxicity seen when Pentoxifylline and radiation are applied together are small and do not exceed a factor of 2.0. The capacity of Pentoxifyline to inhibit homologous recombination repair has not as yet been clinically utilized. A suitable application could be in the treatment of cervical carcinoma where irradiation and cisplatin are standard modality. In vitro data also strongly suggest that regimes where irradiation is used in combination with alkylating drugs may also benefit.

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Figures

Figure 1

Figure 1

Constant field gel electrophoresis (CFGE) repair assay showing influence of Pentoxifylline on fractions of DNA released in response to irradiation dose for the parental CHO-K1 cells and NHEJ-defective xrs1 mutant cell line. Adapted from [6].

References

    1. Assaad NA, Zeng Z, Guan J, Thacke J, Iliakis G. Homologous recombination as a potential target for caffeine radiosensitisation in mammalian cells reduced caffeine radiosensitisation in XRSS2 and XRSCC 3 mutants. Oncogene. 2000;129:5788–5800. doi: 10.1038/sj.onc.1203953. - DOI - PubMed
    1. Bache M, Pigorsch S, Dunst J, Wurl P, Meyer A, Bartel F, Schmidt H, Rath FW, Taubert H. Loss of G2/M arrest correlates with radiosensitisation in 2 human sarcoma cell lines with mutant p53. Int J Cancer. 2001;96:110–117. doi: 10.1002/ijc.1002. - DOI - PubMed
    1. Binder A, Bohm L. Influence of irradiation and pentoxifylline on histone H3 phosphorylation in human tumour cell lines. Cell Prolif. 2002;35:37–47. doi: 10.1046/j.1365-2184.2002.00224.x. - DOI - PMC - PubMed
    1. Binder A, Serafin AM, Bohm L. Abrogation of the G2/M phase block enhances the cytotoxicity of Danourubucin, Melphalan and cisplatin in p53 mant human tumour cells. Radiat Res. 2000;154:640–649. - PubMed
    1. Binder A, Theron T, Donninger H, Parker MI, Bohm L. Radiosensitization and DNA repair inhibition by Pentoxifylline in NIH 3T3 p53 transfectants. Int J Radiat Biol. 2002;78:991–1000. doi: 10.1080/0955300021000016369. - DOI - PubMed

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