In Vitro Carbon Ion Beam and Gemcitabine Chemoradiation in a Mucoepidermoid Carcinoma Cell Line.

BACKGROUND/AIM: To determine the interaction of gemcitabine in chemoradiotherapy with heavy carbon ions in vitro in a mucoepidermoid carcinoma (MEC) cell line. MATERIALS AND METHODS: The human lymphatic MEC metastasis cell line NCI-H292 was used. The cells were treated with photons, carbon ions, and gemcitabine. Survival fractions (SF), apoptosis, and cell cycle progression were analyzed. A paired two-sided t-test was used. Significance was defined as p<0.05. RESULTS: Cell proliferation assays showed a significant reduction in SF for combined photon chemoradiation versus photons only. The linear-quadratic fits of combined therapy with carbon ion dose of 0 to 2.5 Gy led to reductions of mean 15% in SF. The LD50 (lethal radiation dose required to reduce cell survival by 50%) for carbon ions only was 0.7 Gy and for carbon ions with gemcitabine 0.6 Gy. The LD50 for photons (with gemcitabine) was 2.8 Gy (2.0 Gy) and for carbon ions (with gemcitabine) 0.7 Gy (0.6 Gy), resulting in a relative biological effectiveness at 10% cell survival (RBE10) of 3.0 (2.7). Carbon ions and photons reduced S phase and increased G2/M phase cell distribution. Isolated treatment with gemcitabine as well as combination with photons led to prolonged S phase transit, whereas combined treatment with carbon ions led to early accumulation in G2/M phase. A significant increase in the sub-G1 population as a hint of relevant number of apoptotic cells was not observed. CONCLUSION: Gemcitabine showed radiosensitizing effects in combination with photons. The combination of gemcitabine and carbon ions had independent additive effects. Carbon ions only had a RBE10 of 3.0, compared to photons only. The combination of gemcitabine, photon, and carbon ions in patients with MEC seems promising and warrants further investigation.

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential.

Nicotinamide adenine dinucleotide (NAD+) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD+ on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD+-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP+. Prolonged disequilibrium of NAD+ metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD+-regulated physiological responses to stresses, the contribution of NAD+ deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.

Radiotherapy-induced heart disease: a review of the literature.

Radiotherapy as one of the four pillars of cancer therapy plays a critical role in the multimodal treatment of thoracic cancers. Due to significant improvements in overall cancer survival, radiotherapy-induced heart disease (RIHD) has become an increasingly recognized adverse reaction which contributes to major radiation-associated toxicities including non-malignant death. This is especially relevant for patients suffering from diseases with excellent prognosis such as breast cancer or Hodgkin's lymphoma, since RIHD may occur decades after radiotherapy. Preclinical studies have enriched our knowledge of many potential mechanisms by which thoracic radiotherapy induces heart injury. Epidemiological findings in humans reveal that irradiation might increase the risk of cardiac disease at even lower doses than previously assumed. Recent preclinical studies have identified non-invasive methods for evaluation of RIHD. Furthermore, potential options preventing or at least attenuating RIHD have been developed. Ongoing research may enrich our limited knowledge about biological mechanisms of RIHD, identify non-invasive early detection biomarkers and investigate potential treatment options that might attenuate or prevent these unwanted side effects. Here, we present a comprehensive review about the published literature regarding clinical manifestation and pathological alterations in RIHD. Biological mechanisms and treatment options are outlined, and challenges in RIHD treatment are summarized.