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Background: All Nordic countries have national cancer registries collecting data on head and neck cancer (HNC) incidence and survival. However, there is a lack of consensus on how other quality aspects should be monitored. Aims: We conducted a web-based survey to find opportunities for quality control and improvement. Methods: A web-based survey was sent to one otorhinolaryngology – head and neck (ORL–HN) surgeon, and one oncologist at each Nordic university hospital treating HNC. In total, 42 responses from all 21 university hospitals were included. Results: In over half of the university hospitals, an oncologist, an ORL—HN surgeon, a pathologist, a radiologist, and a specialized nurse was always present at the multidisciplinary tumor board (MTB) meeting. Of 42 respondents 35 (83%) agreed that treatment delays were systematically recorded for each patient. Eleven of 21 (52%) oncologists agreed that side-effects of (chemo)radiotherapy were systematically recorded. Less than half of the respondents agreed that complications of surgery, and post-treatment quality of life (QOL) were systematically recorded. Conclusions: In the Nordic countries, the importance of HNC treatment timelines is well acknowledged. There is a lack of consensus on the composition of MTB meeting, and how treatment-related morbidity should be monitored outside clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: At first interim analysis of KEYNOTE-629, health-related quality of life (HRQoL) with pembrolizumab was stable or improved over 48 weeks in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). HRQoL results from the second interim analysis in R/M or locally advanced (LA) cSCC are presented. Methods: Patients received pembrolizumab 200 mg every 3 weeks for ≤ 2 years. Change in EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EQ-5D-5L scores were exploratory end points. Primary analysis was performed at week 12 to ensure adequate completion/compliance. Descriptive analyses were also conducted through weeks 48 and 75 for the LA and R/M cohorts, respectively. Results: At data cutoff (29 July 2020), mean scores in the LA cohort (n = 47) were stable from baseline to week 12 for EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) (−0.27 points [95% confidence interval (CI) −10.93 to 10.39]), physical functioning (−1.29 points [95% CI −8.77 to 6.19]), and EQ-5D-5L visual analog scale (2.06 [95% CI −7.70 to 11.82]). HRQoL remained stable through week 48 in the LA cohort; 76.6% and 74.5% of patients had improved or stable GHS/QoL and physical functioning scores, respectively. HRQoL continued to show stability or improvement through week 75 in the R/M cohort (n = 99); 71.7% and 64.6% of patients had improved or stable GHS/QoL and physical functioning scores, respectively. Conclusions: Pembrolizumab has demonstrated antitumor activity and manageable safety. The current analysis shows pembrolizumab treatment preserved HRQoL. Collectively, these results support pembrolizumab as standard of care for LA or R/M cSCC. Trial Registration: ClinicalTrials.gov, NCT03284424—September 15, 2017. [ABSTRACT FROM AUTHOR]

In the Nordic countries, as in the rest of the world, particle therapy as a radiotherapy modality, is evolving, albeit the hard evidence for the clinical benefit still is scarce. However, a common goal for the Nordic countries is to include a minimum of 80% of the patients treated with particle therapy into clinical trials. In this paper, we summarize the current status of clinical trials involving particle therapy in the Nordic countries, with an overview of both active and coming trials. So far, one is closed for inclusion and data are being analyzed, seven trials are actively recruiting patients and several more trials are underway. No common Nordic trial has yet been designed, nor is in the planning phase, and the authors will discuss the obstacles as well as the opportunities a common Nordic platform may represent. [ABSTRACT FROM AUTHOR]

In this study, we hypothesized that androgen-deprivation therapy (ADT) in prostate cancer, although initially efficient, induces changes in the tumor kinome, which subsequently promote development of castration-resistant (CR) disease. Recognizing the correlation between tumor hypoxia and poor prognosis in prostate cancer, we further hypothesized that such changes might be influenced by hypoxia. Microarrays with 144 kinase peptide substrates were applied to analyze CWR22 prostate carcinoma xenograft samples from ADT-naïve, androgen-deprived (AD), long-term AD (ADL), and CR disease stages. The impact of hypoxia was assessed by matching the xenograft kinase activity profiles with those acquired from hypoxic and normoxic prostate carcinoma cell cultures, whereas the clinical relevance was evaluated by analyzing prostatectomy tumor samples from patients with locally advanced disease, either in ADT-naïve or early CR disease stages. By using this novel peptide substrate microarray method we revealed high kinase activity mediated by signal transducer and activator of transcription 5A (STAT5A) in CR prostate cancer. Additionally, we uncovered high STAT5A kinase activity already in regressing ADL xenografts, before renewed CR growth was evidenced. Finally, since increased STAT5A kinase activity also was detected after exposing prostate carcinoma cells to hypoxia, we propose long-term ADT to induce tumor hypoxia and stimulate STAT5A kinase activity, subsequently leading to renewed CR tumor growth. Hence, the study detected STAT5A as a candidate to be further investigated for its potential as marker of advanced prostate cancer and as possible therapeutic target protein. [ABSTRACT FROM AUTHOR]

Background: In early-phase studies with targeted therapeutics and radiotherapy, it may be difficult to decide whether an adverse event should be considered a dose-limiting toxicity (DLT) of the investigational systemic agent, as acute normal tissue toxicity is frequently encountered with radiation alone. We have reanalyzed the toxicity data from a recently conducted phase 1 study on vorinostat, a histone deacetylase inhibitor, in combination with pelvic palliative radiotherapy, with emphasis on the dose distribution within the irradiated bowel volume to the development of DLT.Findings: Of 14 eligible patients, three individuals experienced Common Terminology Criteria of Adverse Events grade 3 gastrointestinal and related toxicities, representing a toxicity profile vorinostat has in common with radiotherapy to pelvic target volumes. For each study patient, the relative volumes of small bowel receiving radiation doses between 6 Gy and 30 Gy at 6-Gy intervals (V6-V30) were determined from the treatment-planning computed tomography scans. The single patient that experienced a DLT at the second highest dose level of vorinostat, which was determined as the maximum-tolerated dose, had V6-V30 dose-volume estimates that were considerably higher than any other study patient. This patient may have experienced an adverse radiation dose-volume effect rather than a toxic effect of the investigational drug.Conclusions: When reporting early-phase trial results on the tolerability of a systemic targeted therapeutic used as potential radiosensitizing agent, radiation dose-volume effects should be quantified to enable full interpretation of the study toxicity profile. [ABSTRACT FROM AUTHOR]

Background. Signet-ring cell carcinoma (SRCC) is an uncommon tumor entity in rectal cancer, often considered to be resistant to non-surgical therapy. In locally advanced primary or recurrent rectal cancer, diagnostic information from magnetic resonance imaging (MRI) is considered superior in planning the optimal treatment strategy, which usually includes preoperative radiotherapy. The recognition of MRI features that correlate with the radiation response might ultimately be used to select patients for tailored treatment and, in addition, avoid potentially toxic therapy in non-responding patients. Material and methods. In a cohort of 120 rectal cancer patients who had received preoperative radiotherapy (50 Gy in 2 Gy fractions), six patients were noted to have SRCC tumor differentiation. Initial diagnostic MRI examination included assessment of local T- and N-stage and tumor morphology. Histological tumor response was subsequently assessed in the resected specimens, and postoperative follow-up data was compiled until disease recurrence. Results. Following the preoperative radiotherapy, two distinctly different histological responses – complete response (ypT0N0) or no response – were observed. Extensive mesorectal lymph node metastasis (N2 disease) at the pretreatment MRI examination was unambiguously associated with lack of response and rapid development of disseminated disease. Importantly, patients with complete response have been observed for 23–52 months postoperatively without evidence of recurrent disease. Discussion. Our review may suggest that patients with locally advanced growth of rectal SRCC, despite poorer outcome when compared to patients with conventional-type rectal adenocarcinoma, when presenting limited lymph node disease should be offered preoperative radiotherapy in a tentatively curative setting. [ABSTRACT FROM AUTHOR]

The tumor cell defense response to ionizing radiation involves a temporary arrest at the cell cycle G2 checkpoint, which is activated by a signaling cascade initiated by the ATM kinase response to DNA damage, ultimately leading to the outcome of further cell survival if the DNA is properly repaired. The inhibitory targeting of the checkpoint kinase signaling elicited by ATM may define a biologically based strategy to override the G2 phase delay that prevents mitotic entry after DNA damage, thereby increasing the probability of mitotic cell death following exposure to ionizing radiation.Breast carcinoma cell lines with intact or defective function of the tumor-suppressor protein BRCA1 were exposed to ionizing radiation in the absence or presence of a specific inhibitor (UCN-01) of the checkpoint kinase CHK1, and the response profiles of cell cycle distribution and G2 phase regulatory factors, as well as the efficiency of clonogenic regrowth, were analyzed.The radiation-induced G2 phase accumulation was preceded by a transient down-regulation of the G2 phase-specific polo-like kinase-1 and cyclin B1, which required intact function of both BRCA1 and CHK1. The concomitant treatment with UCN-01 seemed to amplify the cytotoxic effect of ionizing radiation on clonogenic regrowth.The effector mechanism of DNA damage on cell cycle gene regulation signals through the checkpoint kinase network. Among molecular cell cycle-targeted drugs currently in pipeline for testing in early phase clinical trials, CHK1 inhibitors may have therapeutic potential as radiosensitizers. [Copyright &y& Elsevier]

DNA damage activates the G2 cell cycle checkpoint to allow time for DNA repair before mitotic entry. The mechanism involves inhibition of the enzymatic activity for polo-like kinase 1 (Plk1), rendering Cdc25C with a basal phosphatase activity that is insufficient for converting Cdc2 to the fully active G2/M transition kinase. We found that cell cycle arrest at the G2/M boundary after ionizing radiation (IR) of breast carcinoma cells may involve repression of the gene for Plk1, PLK, mediated by the tumor-suppressor protein BRCA1. The p53-defective MT-1 cell line had an apparent accumulation of G2/M?phase cells 12?h after irradiation. This response was preceded by a transient downregulation of PLK mRNA expression with a barely detectable level 6?h after exposure to IR but recovered after 12?h. A significantly lower fraction of irradiated BRCA1-/- HCC1937 cells arrested in the G2/M?phase after 12?h, and the transient response of PLK mRNA was also considerably impaired. After reconstitution of wild-type BRCA1 in the HCC1937 cells however, downregulation of PLK mRNA as well as Plk1 protein expression after IR was restored. Moreover, the suppression of PLK mRNA expression 6?h after irradiation was completely abolished by the specific CHEK1 kinase inhibitor UCN-01, further indicating that the effector mechanism of DNA damage on PLK signals through BRCA1 and its downstream CHEK1. Our observations provide new information about the diversity of regulatory mechanisms governed by BRCA1 in DNA damage checkpoint control.Oncogene (2003) 22, 8952-8955. doi:10.1038/sj.onc.1207000 [ABSTRACT FROM AUTHOR]

Objective  Squamous cell carcinoma (SCC) of the paranasal sinuses is usually diagnosed at an advanced stage, making curative therapy difficult. The goal of this study was to evaluate the management and outcomes of patients with SCC treated at our institution. Methods  In a population-based consecutive prospective cohort, we conducted an analysis of all patients treated for SCC between 1988 and 2017. Results  A total of 72 patients were included, follow-up was 100%. Mean follow-up was 57 months for the entire cohort, and 108 months for patients with no evidence of disease. Eighty-two percent of all patients had high-stage (T4) disease. Fifty-seven patients underwent treatment with curative intent; consisting of surgery with or without oncologic treatment in 34, and of oncologic treatment only in 23 cases. Fifteen patients received palliative treatment. The rates of overall survival for the entire cohort were 55% at 2, 41% at 5, and 32% at 10 years, and corresponding disease-specific survival (DSS) rates were 55, 45, and 34%, respectively. DSS rates after surgical treatment with curative intent were 81% at 2, 65% at 5, and 54% at 10 years. Retromaxillary involvement and nonradical surgery were negative prognostic factors. Best survival was achieved with the combination of radical surgery and adjuvant oncologic treatment. Conclusion  Surgical resection with a curative intent yielded 65% at 5-year DSS even in this cohort of patients with high-stage SCC and is still considered as the treatment of choice, preferably in combination with adjuvant radiation therapy and chemotherapy. [ABSTRACT FROM AUTHOR]

Objectives  Sinonasal adenocarcinoma (AC) is a potentially curable disease despite being an aggressive malignancy. Long-term survival can be achieved with early diagnosis and adequate multidisciplinary treatment. Our goal was to evaluate outcomes for patients with AC treated at our institution. Design  In a population-based consecutive prospective cohort, we conducted an analysis of all patients treated for surface epithelial AC between 1995 and 2018. Results  Twenty patients were included, and follow-up was 100%. The mean follow-up time was 89 months for the entire cohort (112 months for patients with no evidence of disease). Intestinal-type AC was found in 65%, whereas nonintestinal-type AC was found in 35% of all cases; 75% had stage T3/4 disease. Tumor grade was intermediate/high in 65%. Eighteen patients underwent treatment with curative intent (craniofacial resection [CFR] in 61%, transfacial approach in 39%, adjuvant radiotherapy in 89%), achieving negative margins in 56% of cases. Overall survival (OS) rates were 90, 68, and 54% after 2, 5, and 10 years of follow-up, respectively, and the corresponding disease-specific survival (DSS) rates were 90, 73, and 58%. Age over 60 years, tumor with a maxillary origin, and microscopic bone invasion were negative prognostic factors. Radical CFR was correlated with better OS and DSS. Conclusion  The high probability of achieving radicality with CFR, the low complication rate, the acceptable toxicity of modern irradiation modalities, and the promising survival rates indicate that this strategy might be considered a safe and an effective option for treating patients with very advanced sinonasal AC. [ABSTRACT FROM AUTHOR]

The article focuses on the diagnosis of locally recurrent head and neck squamous cell carcinoma (LRC) in Nordic Head and Neck Cancer (HNC) centers and the feasibility of using the Odense-Birmingham definition for uniform diagnosis. Topics discussed include the variation in clinical practice for classifying LRC versus second primary carcinoma (SPC) and the impact of introducing the Odense-Birmingham definition on diagnostic decisions among HNC specialists.

• Tumor volume, SLC3A2 and CD44 are prognostic for high-dose failure in HNSCC. • SLC3A2 is a biomarker for high-dose failure in (C-)RT for p16 + oropharyngeal SCC. • Tumor volume is the main driver for high-dose failure in p16- HNSCC. • Tumor hypoxia was not prognostic in patients treated with concomitant nimorazole. Reliable and accessible biomarkers for patients with Head and Neck Squamous Cell Carcinoma (HNSCC) are warranted for biologically driven radiotherapy (RT). This study aimed to investigate the prognostic value of putative cancer stem cell (CSC) markers, hypoxia, and tumor volume using loco-regional high-dose failure (HDF) as endpoint. Tumor tissue was retrieved from patients treated with primary chemo-(C-)RT and nimorazole for HNSCC in the Danish Head and Neck Cancer Study Group (DAHANCA) 19 study. Tumor volume, hypoxic classification, and expression of CSC markers CD44, SLC3A2 , and MET were analyzed. For patients with eligible data on all parameters (n = 340), the risk of HDF following primary chemo-(C-)RT were analyzed by these biomarkers as a whole and stratified for p16-positive oropharynx (p16 + OPSCC) vs p16-negative (p16-) tumors (oral cavity, p16- oropharynx, hypopharynx and larynx). Higher risk of HDF was seen for patients with larger primary and nodal volume (>25 cm3, Hazard Ratio (HR): 3.00 [95 % CI: 1.73–5.18]), high SLC3A2 (HR: 2.99 [1.28–6.99]), CD44 (>30 % positive, HR: 2.29 [1.05–5.00]), and p16- tumors (HR: 2.53 [1.05–6.11]). p16- tumors had a higher CSC marker expression than p16 + OPSCC. The factors associated with the highest risk of HDF were larger volume (HR: 3.29 [1.79–6.04]) for p16- tumors (n = 178) and high SLC3A2 (HR: 6.19 [1.58–24.23]) for p16 + OPSCC (n = 162). Tumor volume, p16, and CSC markers are potential biomarkers for HDF for patients with HNSCC treated with (C-)RT. Lower expression of CSC in p16 + OPSCC may contribute to better tumor control. [ABSTRACT FROM AUTHOR]

Background: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.Methods: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.Findings: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], p<0·0001) at final analysis. Neither pembrolizumab alone nor pembrolizumab with chemotherapy improved progression-free survival at the second interim analysis. At final analysis, grade 3 or worse all-cause adverse events occurred in 164 (55%) of 300 treated participants in the pembrolizumab alone group, 235 (85%) of 276 in the pembrolizumab with chemotherapy group, and 239 (83%) of 287 in the cetuximab with chemotherapy group. Adverse events led to death in 25 (8%) participants in the pembrolizumab alone group, 32 (12%) in the pembrolizumab with chemotherapy group, and 28 (10%) in the cetuximab with chemotherapy group.Interpretation: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.Funding: Merck Sharp & Dohme. [ABSTRACT FROM AUTHOR]

Objectives: To assess health-related quality of life (HRQoL) with first-line pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the phase 3 KEYNOTE-048 trial (NCT02358031).Materials and Methods: HRQoL was measured using the European Organisation for Research and Treatment of Cancer 30-question quality-of-life (EORTC QLQ-C30), the EORTC 35-question quality-of-life head and neck cancer-specific module (EORTC QLQ-H&N35), and the EuroQol 5-dimension 3-level instruments (EQ-5D-3L). Secondary endpoints included mean change from baseline in EORTC QLQ-C30 global health status/quality of life (GHS/QoL) at week 15 and time to deterioration (TTD) in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing.Results: Of 882 enrolled participants, 844 received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment; adherence was ≥ 79% at week 15 across treatment groups. At week 15, EORTC QLQ-C30 GHS/QoL scores remained stable; no clinically meaningful between-group differences were observed (least squares mean difference, pembrolizumab vs cetuximab-chemotherapy, 0.24; 95% CI, -3.34 to 3.82; pembrolizumab-chemotherapy vs cetuximab-chemotherapy, 0.40; 95% CI, -3.46 to 4.26). Median TTD in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing scores was not reached over 51 weeks across groups, showing stable HRQoL. TTD was similar between groups for EORTC QLQ-C30 GHS/QoL (pembrolizumab vs cetuximab-chemotherapy: HR, 1.38; 95% CI, 0.95-2.00; pembrolizumab-chemotherapy vs cetuximab-chemotherapy: HR, 1.37; 95% CI, 0.94-2.00), as was TTD in EORTC QLQ-H&N35 pain and swallowing scores.Conclusions: Pembrolizumab monotherapy and pembrolizumab-chemotherapy extended OS while maintaining HRQoL, further supporting first-line use for R/M HNSCC. [ABSTRACT FROM AUTHOR]

Objective: The PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA) study is a randomized, placebo-controlled, double-blind trial to determine whether angiotensin receptor blockers (ARB), or beta-blockers or their combination may prevent the development of left ventricular (LV) dysfunction in patients on standard adjuvant treatment for early breast cancer. Methods: Following surgical resection, 120 breast cancer patients scheduled for adjuvant epirubicin-containing chemotherapy and, if indicated, trastuzumab, will be included. They will be randomized to an ARB (candesartan), a beta-blocker (metoprolol) and matching placebos in a 2 × 2 factorial design. The primary objective of the PRADA study is to assess whether prophylactic ARB and/or beta-blockers may prevent a reduction in LV ejection fraction (EF) after adjuvant treatment of early breast cancer, as evaluated by serial cardiovascular magnetic resonance (CMR) performed at randomization, after the first chemotherapy cycle and on its completion, and for subgroups, on completion of radiotherapy or trastuzumab. Secondary outcome measures include echocardiographic indices of LV diastolic dysfunction, structural myocardial alterations assessed by CMR and changes in cardiac biomarkers. Conclusion: PRADA may provide new information on the prophylactic effect of ARB and beta-blockers in patients with early breast cancer regarding the risk of developing cardiac dysfunction from adjuvant cancer treatment. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The tumor response to preoperative radiotherapy of locally advanced rectal cancer varies greatly, warranting the use of experimental models to assay the efficacy of molecular targeting agents in rectal cancer radiosensitization. Histone deacetylase (HDAC) inhibitors, agents that cause hyperacetylation of histone proteins and thereby remodeling of chromatin structure, may override cell cycle checkpoint responses to DNA damage and amplify radiation-induced tumor cell death. Methods: Human colorectal carcinoma cell lines were exposed to ionizing radiation and HDAC inhibitors, and cell cycle profiles and regulatory factors, as well as clonogenicity, were analyzed. Results: In addition to G2/M phase arrest following irradiation, the cell lines displayed cell cycle responses typical for either intact or defective p53 function (the presence or absence, respectively, of radiation-induced expression of the cell cycle inhibitor p21 and subsequent accumulation of G1 phase cells). In contrast, histone acetylation was associated with complete depletion of the G1 population of cells with functional p53 but accumulation of both G1 and G2/M populations of cells with defective p53. The cellular phenotypes upon HDAC inhibition were consistent with the observed repression of Polo-like kinase-1, a regulatory G2/M phase kinase. Following pre-treatment with HDAC inhibitors currently undergoing clinical investigation, the inhibitory effect of ionizing radiation on clonogenicity was significantly amplified. Conclusion: In these experimental models, HDAC inhibition sensitized the tumor cells to ionizing radiation, which is in accordance with the concept of increased probability of tumor cell death when chromatin structure is modified. [ABSTRACT FROM AUTHOR]

Abstract: A senescence-like growth arrest succeeded by recovery of proliferative capacity was observed in MCF-7 breast tumor cells exposed to fractionated radiation, 5×2Gy. Exposure to EB 1089, an analog of the steroid hormone 1α, 25 dihydroxycholecalciferol (1α, 25 dihydroxy Vitamin D3; calcitriol), prior to irradiation promoted cell death and delayed both the development of a senescent phenotype and the recovery of proliferative capacity. EB 1089 also reduced clonogenic survival over and above that produced by fractionated radiation alone and further conferred susceptibility to apoptosis in MCF-7 cells exposed to radiation. In contrast, EB 1089 failed to enhance the response to radiation (or to promote apoptosis) in normal breast epithelial cells or BJ fibroblast cells. EB 1089 treatment and fractionated radiation additively promoted ceramide generation and suppressed expression of polo-like kinase 1. Taken together, these data indicate that EB 1089 (and 1α, 25 dihydroxycholecalciferol or its analogs) could selectively enhance breast tumor cell sensitivity to radiation through the promotion of cell death, in part through the generation of ceramide and the suppression of polo-like kinase. [Copyright &y& Elsevier]