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@ARTICLE{Yaromina:276868,
      author       = {A. Yaromina and L. Koi and L. Schuitmaker and A. M. A. van
                      der Wiel and L. J. Dubois and M. Krause$^*$ and P. Lambin},
      title        = {{O}vercoming radioresistance with the hypoxia-activated
                      prodrug {CP}-506: a pre-clinical study of local tumour
                      control probability.},
      journal      = {Radiotherapy and oncology},
      volume       = {186},
      issn         = {0167-8140},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier Science},
      reportid     = {DKFZ-2023-01180},
      pages        = {109738},
      year         = {2023},
      note         = {Volume 186, September 2023, 109738},
      abstract     = {Tumour hypoxia is an established radioresistance factor. A
                      novel hypoxia-activated prodrug CP-506 has been proven to
                      selectively target hypoxic tumour cells and to cause
                      anti-tumour activity. The current study investigates whether
                      CP-506 improves outcome of radiotherapy in vivo.Mice bearing
                      FaDu and UT-SCC-5 xenografts were randomized to receive 5
                      daily injections of CP-506/vehicle followed by single dose
                      (SD) irradiation. In addition, CP-506 was combined once per
                      week with fractionated irradiation (30 fractions/6 weeks).
                      Animals were followed-up to score all recurrences. In
                      parallel, tumours were harvested to evaluate pimonidazole
                      hypoxia, DNA damage (γH2AX), expression of
                      oxidoreductases.CP-506 treatment significantly increased
                      local control rate after SD in FaDu, $62\%$ vs. $27\%$
                      (p=0.024). In UT-SCC-5, this effect was not curative and
                      only marginally significant. CP-506 induced significant DNA
                      damage in FaDu (p=0.009) but not in UT- SCC-5. Hypoxic
                      volume (HV) was significantly smaller (p=0.038) after
                      pretreatment with CP-506 as compared to vehicle in FaDu but
                      not in less responsive UT-SCC-5. Adding CP-506 to
                      fractionated radiotherapy in FaDu did not result in
                      significant benefit.The results support the use of CP-506 in
                      combination with radiation in particular using
                      hypofractionation schedules in hypoxic tumours. The
                      magnitude of effect depends on the tumour model, therefore
                      it is expected that applying appropriate patient
                      stratification strategy will further enhance the benefit of
                      CP-506 treatment for cancer patients. A phase I-IIA clinical
                      trial of CP-506 in monotherapy or in combination with
                      carboplatin or a checkpoint inhibitor has been approved
                      (NCT04954599).},
      keywords     = {Hypoxia (Other) / Hypoxia-activated prodrug CP-506 (Other)
                      / Radiotherapy (Other) / local control (Other) / xenografts
                      (Other)},
      cin          = {DD01},
      ddc          = {610},
      cid          = {I:(DE-He78)DD01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37315579},
      doi          = {10.1016/j.radonc.2023.109738},
      url          = {https://inrepo02.dkfz.de/record/276868},
}