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Non-platinum based halogenated compounds – preliminary preclinical evaluation in murine and human pancreatic cancer
13 August 2018 (online)
Pancreatic ductal adenocarcinoma (PDA) is highly resistance to standard chemo- and radiotherapy. Recently, in vitro and in vivo studies discovered a new class of non-platinum-based halogenated molecules that selectively kill cancer cells. 1,2-Diamino-4,5-dibromobenzene (DAB) has not been tested in PDA.
Human and murine pancreatic cancer cell lines (Panc1, Patu, MiaPaca, BxPC3 and 4 different KPC cell lines) were treated with different concentrations of DAB and ionizing radiation followed by MTT assays. Furthermore, cells were treated with 25µM DAB and 2 Gy for clonogenic assays. For in vivo studies the KrasG12D/+; pdx-1-Cre (KC) model was treated for 2 months with DAB (7 mg/kg, i.p.) weekly. Moreover, tumor-bearing LSL-KrasG12D/+; LSL-Trp53R172 H/+; pdx-1-Cre (KPC) mice were treated over 10 d with DAB (7 mg/kg, i.p.), Gemcitabine (100 mg/kg, i.p.) or combination of both. Tumor volume was evaluated by high resolution ultrasound at day 7 and day 10.
Cell viability was significantly reduced in all human pancreatic cancer cell lines with GI50 values between 20 – 150µM. Comparable effects were obtained for murine cell lines. Colony formation in human BxPC3 cell line was 15fold decreased upon 25µM DAB treatment (72,5 ± 7,5 colonies vs. 547,5 ± 31,5 colonies, p = 0,004). However, only Panc1 showed synergistic effects by the combination of irradiation and DAB treatment. Pilot studies showed very good tolerability of DAB in KC mice. Upon DAB treatment the tumor volume in KPC mice was not significantly reduced compared to gemcitabine (1,476 mm3± 0,1135 mm3 vs. 1,337 mm3± 0,1917 mm3). Furthermore, combination of gemcitabine and DAB did not show any effect on tumor volume reduction.
DAB was effective in killing human and murine pancreatic cancer cells in vitro. Synergistic effects in combination with ionizing radiation were not achieved. In vivo, effects were comparable with gemcitabine monotherapy, but combination of both drugs was not synergistic. Ongoing studies investigate the combination of radiation and DAB in in vivo.