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BACKGROUND: This work investigates on putative cytotoxic effects in four different hepatocellular carcinoma (HCC) cell lines after irradiation with photons or carbon ions in combination with new targeted molecular therapy using either Temsirolimus (TEM) or Gemcitabine (GEM). METHODS AND MATERIALS: The HCC cell lines HepG2, Hep3B, HuH7, and PLC were cultured and irradiated with photons or carbon ions at the Heidelberg Ion Beam Therapy Center using the raster-scanning method. For combination experiments, cell lines were first treated with Temsirolimus or GEM before irradiation. Cytotoxicity was measured by a clonogenic survival assay. The evaluation of the experiments and the obtained survival curves were based on the concept of additivity defined by Steel and Peckham. RESULTS: The results for the combination of carbon ions and both tested systemic substances TEM and GEM showed independent toxicities in all four cell lines. Supra-additive effects were observed in PLC cells for photon irradiation combined either with TEM or GEM and in HuH7 cells for the combination of photons with TEM. CONCLUSION: Addition of targeted therapy substances Temsirolimus and GEM to photon irradiation showed additive cytotoxicity in HCC cell lines, whereas independent toxicities where reached by the combination of carbon ions to these substances. It can be assumed that combining 12C with systemic substances only has independent effects because heavy ions cause direct damage because of their high-LET character resulting in complex and clustered double-strand breaks. Nonetheless, further investigations are warranted in order to determine whether addition of systemic therapy allows a reduction of radiation doses in combination therapy. This could possibly lead to better responses and tolerances in patients with HCC.
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AIMS AND BACKGROUND: Heavy ion therapy has shown promising results in the treatment of recurrent colorectal carcinoma. The present study evaluates the effect of five different cytostatic agents in combination with radiotherapy with carbon (C12) ions and photons in two isogenic colorectal cancer cell lines differing in p53 status. METHODS AND STUDY DESIGN: Clonogenic survival analyses were performed using the human colon cancer cell lines HCT 116 wt and the isogenic p53 deficient cell line HCT 116 p53 -/-. Single photon doses (6 MV X-rays) up to 10 Gy were applied using a linear accelerator. Carbon ion irradiation up to 3 Gy was performed at the Heidelberg Ion-Beam Therapy Center with the horizontal beamline delivering an extended Bragg peak with an average linear energy transfer of 103 keV/µm. Five different cytostatic agents were applied in combinations with photon and carbon ion radiotherapy. RESULTS: Both cell lines showed a similar response to photons and carbon ions, whereas treatment with carbon ions resulted in a superior relative biological efficiency. Irinotecan and paclitaxel alone showed high toxicity in the treatment of wildtype cells. A notable difference was observed on the cell death of p53 -/- cell lines. Here, single treatment with paclitaxel and gemcitabine resulted in good response rates. Combinations of carbon ions with gemcitabine, irinotecan or paclitaxel revealed high response rates. After irradiation with carbon ions and temozolomide, cell survival rates depended on p53 status, with a decreased survival rate in wildtype cells. CONCLUSIONS: Irinotecan and paclitaxel are an effective treatment for HCT 116 wt cells, whereas HCT 116 cells with p53 deficiency can be treated successfully with paclitaxel and gemcitabine. Combined treatment modalities with carbon ions and chemotherapy provide great effectiveness that may offer new treatment opportunities for recurrent colorectal cancer in the future.
