Current Management Practices for Endometrial Cancer (EC) in the UK: A National Healthcare Professional Survey (KNOW-EC).

The clinical landscape for endometrial cancer in the UK is evolving to include new management guidelines and targeted treatment options. An understanding of current treatment and management practices in the UK will help services plan and adapt to upcoming changes. AIM: The purpose of this survey was to understand current and anticipated real-world practices for endometrial cancer care in the UK and potential areas for optimisation. MATERIALS AND METHODS: Telephone interviews were conducted in November/December 2021 with UK-based healthcare professionals involved in endometrial cancer management. Questions were aligned with the British Gynaecological Cancer Society/European Society for Medical Oncology recommendations, covering the pathway from diagnosis and treatment to follow-up. RESULTS: A total of 63 healthcare professionals (HCPs) involved in the management of patients with endometrial cancer participated in telephone interviews. The results highlighted variations in management and treatment practices for endometrial cancer and suggest that current UK practice appears to diverge from national and international guidance in some instances. While somatic mismatch repair deficiency testing was used by 89.7% of respondents as mainstream testing, the survey highlighted a lack of access to other key molecular biomarker tests, such as polymerase epsilon (POLE) sequencing (used by only 9.8% of HCPs at the time of the survey). CONCLUSION: The results highlighted several perceived practical barriers to the swift adoption of new therapeutic options, including funding access, limited staff, treatment-related resources, staff education, and support. Our findings support the need for better access to biomarkers that could enable more effective and targeted treatments.

Hitting the Target: Developing High-quality Evidence for Proton Beam Therapy Through Randomised Controlled Trials.

The National Health Service strategy for the delivery of proton beam therapy (PBT) in the UK provides a unique opportunity to deliver high-quality evidence for PBT through randomised controlled trials (RCTs). We present a summary of three UK PBT RCTs in progress, including consideration of their key design characteristics and outcome assessments, to inform and support future PBT trial development. The first three UK multicentre phase III PBT RCTs (TORPEdO, PARABLE and APPROACH), will compare PBT with photon radiotherapy for oropharyngeal squamous cell carcinoma, breast cancer and oligodendroglioma, respectively. All three studies were designed by multidisciplinary teams, which combined expertise from clinicians, clinical trialists and scientists with strong patient advocacy and guidance from national radiotherapy research networks and international collaborators. Consistent across all three studies is a focus on the reduction of long-term radiotherapy-related toxicities and an evaluation of patient-reported outcomes and health-related quality of life, which will address key uncertainties regarding the clinical benefits of PBT. Innovative translational components will provide insights into mechanisms of toxicity and help to frame the key future research questions regarding PBT. The UK radiotherapy research community is developing and delivering an internationally impactful PBT research portfolio. The combination of data from RCTs with prospectively collected data from a national PBT outcomes registry will provide an innovative, high-quality repository for PBT research and the platform to design and deliver future trials of PBT.

The detection of germline and somatic BRCA1/2 genetic variants through parallel testing of patients with high-grade serous ovarian cancer: a national retrospective audit.

OBJECTIVE: To determine the frequency of germline and somatic pathogenic BRCA1 and BRCA2 variants in patients with high-grade serous ovarian cancer tested by next-generation sequencing (NGS), with the aim of defining the best strategy to be implemented in future routine testing. DESIGN: National retrospective audit. SETTING: The All Wales Medical Genomics Service (AWMGS). POPULATION: Patients with high-grade serous ovarian/fallopian tube/peritoneal cancer referred by oncologists to the AWMGS between February 2015 and February 2021 for germline and/or tumour testing of the BRCA1 and BRCA2 genes by NGS. METHODS: Analysis of NGS data from germline and/or tumour testing. MAIN OUTCOME MEASURES: Frequency of BRCA1 and BRCA2 pathogenic variants. RESULTS: The overall observed germline/somatic pathogenic variant detection rate was 11.6% in the 844 patients included in this study, with a 9.2% (73/791) germline pathogenic variant detection rate. Parallel tumour and germline testing was carried out for 169 patients and the overall pathogenic variant detection rate for this cohort was 14.8%, with 6.5% (11/169) shown to have a somatic pathogenic variant. Two BRCA1 dosage variants were found during germline screens, representing 2.0% (2/98) of patients with a pathogenic variant that would have been missed through tumour testing alone. CONCLUSIONS: Parallel germline and tumour BRCA1 and BRCA2 testing maximises the detection of pathogenic variants in patients with high-grade serous ovarian cancer. TWEETABLE ABSTRACT: Parallel germline and tumour testing maximises BRCA pathogenic variant detection in ovarian cancer.

Recurrent Follicular Dendritic Cell Sarcoma of the Parotid Gland Imaged with 18F-FDG PET/CT.

Follicular dendritic cell sarcoma (FDCS) is an extremely rare tumor with only 67 cases of head and neck FDCS reported in the literature. A 65-year-old female had a 6-cm follicular dendritic cell sarcoma resected from the left parotid gland with close margins. It recurred 1 year later as a 5-cm mass that was intensely [18F] fluoro-2-deoxy-D-glucose (18F-FDG) avid on positron emission tomography/computed tomography (PET/CT) and was re-excised. A follow-up PET/CT did not show any metastatic disease. The use of 18F-FDG PET/CT in the management of FDCS warrants further research. We present the 18F-FDG PET/CT imaging findings of this rare tumor.

Simplified staging laparotomy in FIGO stage 1 epithelial ovarian cancer: follow-up and outcomes in south Wales, U.K.

We have conducted a retrospective analysis of FIGO stage 1 ovarian cancer patients in south Wales, who underwent a simplified staging laparotomy without routine nodal sampling and peritoneal biopsies. Patient records from January 2004 to December 2010 were analysed. A total of 116 patients were included in the final analysis. Adjuvant chemotherapy was offered to patients with risk factors for relapse (grade > 1, clear cell histology, or stage > Ia); overall, 89 patients (76.7%) received adjuvant single agent carboplatin (n = 54, 46.5%) or combination chemotherapy (n = 35, 30.2%). After a median follow up of 41 months (range 12-95), 18 patients have relapsed (15.5%), of these 17 had risk factors and 16 had received adjuvant chemotherapy. Eighteen patients have died, of whom 6 of non-cancer related causes without prior relapse. 5-year overall and relapse free survival were 80%. In conclusion, in situations where there are limited resources and operating time constraints, our data suggest that a simplified staging laparotomy approach may be a reasonable compromise in apparently early stage ovarian cancer: this may result in a more aggressive use of chemotherapy, but survival outcomes seem comparable to other series.

Quality of induced sputum using a human-powered nebuliser in a mobile human immunodeficiency virus testing service in South Africa.

OBJECTIVES: To investigate the quality of induced sputum samples using a human-powered (HPN) and an electric-powered nebuliser (EPN). METHODS: For each participant two sputum samples were induced using the HPN and the EPN. The sequence of the two nebulisers was allocated at random. The proportion of good quality sputum according to different assessment criteria was compared using an exact McNemar test. The difference in time to expectoration was compared using the Wilcoxon matched-pairs signed-rank test. RESULTS: A total of 123 individuals were eligible for the study. Nine individuals refused to participate and five were unable to produce a sputum sample. The proportion of good quality sputum was higher among sputum samples induced by the HPN compared to those obtained using the EPN. The median time to produce a sputum sample was 2.2 min (IQR 1.13-4.1) for the HPN and 2.5 min (IQR 1.4-4.1) for the EPN. CONCLUSION: The HPN induced good quality sputum within 3 min. The device operates without electricity and is suitable not only for remote clinics with unreliable electricity, but also for mobile services and community-based intensified tuberculosis (TB) case finding. Further research needs to investigate the yield of TB in sputum samples induced by the HPN.

Induction chemotherapy followed by chemoradiation in locally advanced pancreatic cancer: an effective and well-tolerated treatment.

AIMS: The treatment of locally advanced pancreatic cancer varies enormously both within the UK and internationally. Although chemoradiation is the treatment of choice in the USA, in the UK this modality is used infrequently because of concerns regarding both its efficacy and its toxicity. We reviewed our experience with induction chemotherapy and selective chemoradiation in an attempt to show that it is a well-tolerated treatment that may be superior to chemotherapy alone. MATERIALS AND METHODS: Case notes of patients with locally advanced pancreatic cancer referred to the Velindre Cancer Centre between 1 March 2005 and 31 October 2007 were reviewed. Data on patient demographics, tumour characteristics, treatment and overall survival were collected retrospectively. Toxicity data during chemoradiation were collected prospectively. Patients who had non-progressive disease after 3 months of chemotherapy were planned for chemoradiation using three-dimensional conformal radiotherapy to a total dose of 4500-5040cGy in 25-28 daily fractions with gemcitabine as a radiosensitiser. RESULTS: Of the 91 referrals, 69 (76%) were fit for active oncological treatment; 43/69 (62%) patients were considered for induction chemotherapy followed by chemoradiation and 16/43 (37%) patients received chemoradiation. The median overall survival for patients receiving primary chemotherapy (n=26) was 9.2 (6.8-11.9) months and was 15.3 (11.6-upper limit not reached) months for patients who received chemoradiation (n=16). During the induction chemotherapy 8/16 (50%) patients experienced grade 3/4 toxicity and there were five hospital admissions. During chemoradiation there were 6/16 (37.5%) cases of grade 3/4 toxicity and two hospital admissions. There were no treatment-related deaths. Overall, 94.5% of the intended radiotherapy dose and 84% of the concurrent chemotherapy dose was delivered. CONCLUSIONS: In this UK network, about half of patients were considered for chemoradiation, but only 18% received it. Survival and treatment-related toxicity are consistent with data from other chemoradiation trials and in our series chemoradiation was tolerated better than chemotherapy alone. This supports the view that 'consolidation' chemoradiation is a viable treatment option that should be considered in selected patients with locally advanced non-metastatic pancreatic cancer.

Gemcitabine and carboplatin in the treatment of transitional cell carcinoma of the urothelium: a single centre experience and review of the literature.

The objectives of this study are to evaluate patient outcomes in clinical practice using gemcitabine and carboplatin (GCarbo) as first-line treatment in metastatic transitional cell carcinoma (TCC) of the urothelium, and to review the published evidence on the use of GCarbo in this setting. From July 2003, all cases of metastatic TCC of the urothelium referred to a single consultant were treated using 3-weekly gemcitabine 1200 mg/m(2) i.v. days 1 and 8 plus carboplatin AUC 5-6 i.v. day 1 to a maximum of six cycles. Fifteen patients (median age 67 years) were treated. Grade 3 or 4 toxicity included neutropenia (47%), anaemia (27%) and thrombocytopenia (20%). No patients required admission for neutropenic pyrexia/sepsis, and there were no treatment-related deaths. The overall response rate was 67%. The median survival was 9 months (95% CI 7.4-10.6), and 1-year survival 42%. Gemcitabine and carboplatin is well tolerated, and has activity as first-line treatment in metastatic TCC of the urothelium. However, there is now evidence suggesting that gemcitabine and cisplatin may be more efficacious, and until the appropriate randomized phase 3 trials have been carried out, gemcitabine and cisplatin should probably remain the preferred first-line therapy. Gemcitabine and carboplatin is an effective alternative in those patients not deemed fit enough for cisplatin.

Basaloid carcinoma of the prostate: a case report and review of the literature.

Malignant tumours arising from the basal cells of the prostate gland are extremely rare, and the majority of reports in the literature suggest a relatively indolent clinical course. We report a case of infiltrative basaloid carcinoma of the prostate in a 68-year old man that did not respond to systemic chemotherapy. It is essential that this aggressive disease is differentiated from more indolent basaloid proliferations, as metastatic spread can occur and outcome may be poor.

Radiotherapy after radical prostatectomy for adenocarcinoma of the prostate: a UK institutional experience and review of published studies.

AIMS: The role of radiotherapy to the prostate bed after radical prostatectomy is the subject of much debate. We carried out a retrospective analysis of all patients treated with either adjuvant radiotherapy (ART) or salvage radiotherapy (SRT) in a single UK cancer centre and compared outcomes with published studies. MATERIALS AND METHODS: All patients receiving radiotherapy at any time after a radical prostatectomy were identified and data collected. Patients were referred for ART because of positive surgical margins. SRT was carried out in patients with a detectable or rising prostate-specific antigen (PSA) postoperatively. Patients received either 55 Gy in 20 fractions or 60-64 Gy in 30-32 fractions. All but eight patients were treated using three-dimensional conformal radiotherapy. Both groups were combined for statistical analysis. Biochemical progression-free survival (BPFS) was calculated and displayed using Kaplan-Meier curves. Cox regression was used for univariate and multivariate analysis. RESULTS: In total, 40 patients received postoperative radiotherapy and had a 3-year overall BPFS of 64%. There was no significant difference in 3-year BPFS between ART and SRT (73% vs 61%, P=0.33). Univariate analysis showed that 3-year BPFS was significantly longer if the highest postoperative PSA was<0.5 ng/ml compared with> or =0.5 ng/ml (83% vs 47%, P=0.019), and if the Gleason grade was <7 compared with > or =7 (92% vs 49%, P=0.007). A PSA at diagnosis<10 ng/ml, positive surgical margins, absence of seminal vesicle involvement and neoadjuvant hormones were all associated with a trend towards improved BPFS. Patients with all of these factors had a 3-year BPFS of 91%. Multivariate analysis of the same parameters showed that only Gleason grade remained statistically significant (P=0.019). CONCLUSIONS: The results from this series are in line with published studies, and support the evidence that prostate bed radiotherapy may affect biochemical control in a proportion of patients at risk of relapse. It is not clear whether ART in patients at high risk of relapse or SRT on relapse is most effective.

Pancreatic cancer within a UK cancer network with special emphasis on locally advanced non-metastatic pancreatic cancer.

AIMS: The outcome of patients with pancreatic cancer from an unselected population within a UK region has not previously been reported. We undertook a review of pancreatic cancer in southeast Wales, with an emphasis on locally advanced non-metastatic pancreatic cancer (LANPC) in an attempt to define a subgroup of patients who would probably benefit from multi-modality treatment. MATERIALS AND METHODS: Case notes of patients referred to Velindre Hospital between 1 January 2002 and 31 December 2005 were reviewed. Data on patient demographics, tumour characteristics, treatment, treatment response and overall survival were collected. The Log-rank test was used to compare survival between groups and Cox regression was used to evaluate whether age, gender, tumour site and treatment response correlated with overall survival in LANPC. RESULTS: Of the 354 referrals (complete data on 315 patients), 93% were inoperable and 51% of inoperable patients received active treatment (149/294). One hundred and fourteen patients out of 315 (36%) had LANPC and 72/114 (64%) were fit for active treatment, including chemotherapy (n=66) and chemoradiotherapy (CRT) (n=6). The median survival of patients with LANPC was 7.4 months (95% confidence interval 6.4-8.5). Survival for patients receiving chemotherapy, CRT and no treatment was 9.2 (7.5-10.7), 12.6 (6.1-19.1) and 4.5 (3.7-5.3) months, respectively. Overall survival of patients who had non-progressive disease after initial chemotherapy was significantly better than those who progressed (11.8 vs 6.6 months, P=0.01). Of the 180/315 (57%) patients presenting with metastatic disease, 43% received active treatment. Overall survival of metastatic patients was 2.8 months (2.3-3.2 months); for those receiving active treatment, this was 5.6 months (5.1-6.1 months) and for those receiving active supportive care 1.8 months (1.6-2.0 months). CONCLUSIONS: In this UK network, about half of the patients received active treatment. Although the overall outcome was poor, that of treated patients was comparable with published studies. For patients with LANPC, the initial response or disease stabilisation on chemotherapy defined a subset of patients who had better outcome. The role of CRT over and above chemotherapy needs to be defined through trials that should include a neoadjuvant 'chemotherapy-only' phase to select out patients who benefit from multi-modality treatment.

Predicting the physiological relevance of in vitro cancer preventive activities of phytochemicals.

There is growing interest in the ability of phytochemicals to prevent chronic diseases, such as cancer and heart disease. However, some of these agents have poor bioavailability and many of the in-depth studies into their mechanisms of action have been carried out in vitro using doses which are unachievable in humans. In order to optimize the design of chemopreventive treatment, it is important to determine which of the many reported mechanisms of action are clinically relevant. In this review we consider the physiologically achievable doses for a few of the best studied agents (indole-3-carbinol, diindolylmethane, curcumin, epigallocatechin-3-gallate and resveratrol) and summarize the data derived from studies using these low concentrations in cell culture. We then cite examples of in vitro effects which have been observed in vivo. Finally, the ability of agent combinations to act synergistically or antagonistically is considered. We conclude that each of the compounds shows an encouraging range of activities in vitro at concentrations which are likely to be physiologically relevant. There are also many examples of in vivo studies which validate in vitro observations. An important consideration is that combinations of agents can result in significant activity at concentrations where any single agent is inactive. Thus, for each of the compounds reviewed here, in vitro studies have provided useful insights into their mechanisms of action in humans. However, data are lacking on the full range of activities at low doses in vitro and the benefits or otherwise of combinations in vivo.

Small cell oesophageal carcinoma: an institutional experience and review of the literature.

Primary small cell oesophageal carcinoma (SCOC) is rare, prognosis is poor and there is no established optimum treatment strategy. It shares many clinicopathologic features with small cell carcinoma of the lung; therefore, a similar staging and treatment strategy was adopted. Sixteen cases referred to Velindre hospital between 1998 and 2005 were identified. Patients received platinum-based combination chemotherapy if appropriate. Those with limited disease (LD) received radical radiotherapy (RT) to all sites of disease on completion of chemotherapy. Median survival of all patients was 13.2 months. Median survival of patients with LD was significantly longer than those with extensive disease (24.4 vs 9.1 months, P=0.034). This is one of the largest single institution series in the world literature. Combined modality therapy using platinum-based combination chemotherapy and radical RT may allow a nonsurgical approach to management, avoiding the morbidity of oesophagectomy. Prophylactic cranial irradiation is controversial, and should be discussed on an individual basis.

Bladder preservation in small cell carcinoma of the urinary bladder: an institutional experience and review of the literature.

AIMS: Primary small cell carcinoma (SCC) of the urinary bladder is rare, accounting for less than 1% of all primary bladder malignancies. Metastases are often present at the time of diagnosis, prognosis is poor and there is no established optimum treatment strategy. Small cell carcinoma of the lung (SCLC) shares many clinicopathological features with SCC of the bladder, and there is good evidence supporting the use of combination chemotherapy in SCLC. In addition, consolidation thoracic irradiation and prophylactic cranial irradiation (PCI) both increase 3-year absolute survival by 5.4% in SCLC patients with limited disease and a complete response to chemotherapy. Therefore, we adopted a similar staging and treatment strategy for SCC of the bladder. We report our clinical experience using this strategy, and review published studies. MATERIALS AND METHODS: All cases of SCC of the bladder referred to Velindre Hospital between 1998 and 2005 were identified and data collected retrospectively on demographic details, stage, performance status, treatment and response to treatment. For the review, the electronic databases MEDLINE, EMBASE and Cancerlit were searched, along with hand searching of journals, relevant books and review papers. RESULTS: Seven patients were identified. In total, six out of seven had platinum-based chemotherapy. Four patients received consolidation radiotherapy (CRT) to the bladder after a complete response to chemotherapy, and none have locally relapsed to date. The three patients with limited disease remain alive and disease free 14, 30 and 36 months after diagnosis. CONCLUSIONS: Combined modality therapy using platinum-based combination chemotherapy and consolidation radiotherapy may provide effective local control and allow a bladder-preserving approach to the management of SCC of the bladder. The role of PCI is controversial, and should be discussed with patients on an individual basis.

Small cell lung cancer treated in southeast Wales.

AIMS: In small cell lung cancer (SCLC), consolidation thoracic irradiation (CTI) increases 3-year absolute survival by 5.4% in patients with limited disease and a complete response to chemotherapy. Early concurrent thoracic radiotherapy has been shown to improve local control and prolong survival compared with CTI in some trials. The standard management of patients with SCLC in southeast Wales is CTI in individuals with limited disease and a complete response to chemotherapy. A review of patients with SCLC was carried out to establish whether survival locally is comparable with that reported in published studies, and if patients given CTI have survival comparable with that reported in studies where early concurrent thoracic radiotherapy was used. MATERIALS AND METHODS: Between January 2000 and December 2002, 303 patients were registered with SCLC in southeast Wales. One hundred and fifteen (47%) patients had limited disease and 60/115 (52%) received CTI. RESULTS: Patients with limited disease receiving CTI had a median survival of 17.7 months (95% confidence interval: 15-27.9 months). The 2- and 5-year survivals were 38 and 13%, respectively. CONCLUSIONS: These results compare favourably with previously published studies on SCLC. There are no plans to change our current treatment policy for SCLC in southeast Wales.

Ex vivo cancer chemoprevention research possibilities.

The concept of cancer prevention with naturally occurring or synthetic compounds is rapidly gaining momentum as a key field in cancer research. The availability of good models for the determination of the molecular mechanisms of these agents, which frequently have multiple sites of action within a cell, is key to the progression of the field. In this review, we concentrate on the emergence of several in vitro techniques that have significant advantages over more traditional monolayer cell culture, and/or in vivo models. In particular, we focus on the potential of 3D multicellular spheroid models as versatile intermediates between monolayer culture and tumours in situ. In these models, cell-cell interactions and cell-extracellular matrix interactions can closely mimic the environment to which tumour cells would be exposed in vivo, while maintaining the advantages of ease of manipulation of an in vitro system. The in vitro tube formation assay for the study of angiogenesis, the availability of human tissues for research, and the sophisticated technology surrounding DNA microarray and proteomics are also briefly discussed.

Inhibition of phosphatidylinositol 3-kinase/protein kinase B signaling is not sufficient to account for indole-3-carbinol-induced apoptosis in some breast and prostate tumor cells.

PURPOSE AND EXPERIMENTAL DESIGN: Indole-3-carbinol has been proposed to induce apoptosis via a mechanism involving inhibition of protein kinase B (PKB) signaling in breast and prostate tumor cell lines. However, no functional data exist, and the effect of indole-3-carbinol on viability is known to be highly cell type specific. Here, we examine any requirement for PKB inhibition in induction of apoptosis by indole-3-carbinol in the MDA MB468 cell line using in vitro kinase assays, transfection, Western blotting, and flow cytometry. Comparison is also made with MCF10CA1 breast and PC3 prostate tumor cells. RESULTS: Indole-3-carbinol directly inhibited activity of phosphatidylinositol 3-kinase (PI3K) immunoprecipitated from HBL100 or MDA MB468 cells in vitro. Nonetheless, we present three lines of evidence that inhibition of PI3K/PKB signaling is not required for induction of apoptosis by indole-3-carbinol. First, 50% inhibition of PKB phosphorylation by LY294002 resulted in only 15% apoptosis after 72 hours, whereas similar PKB inhibition by indole-3-carbinol coincided with 30% apoptosis after only 24 hours. Second, induction of phospho-PKB (p-PKB) levels following stimulation with epidermal growth factor did not prevent indole-3-carbinol-induced apoptosis. Third, overexpression of active PKBalpha did not prevent induction of apoptosis by indole-3-carbinol. Inhibition of PKB phosphorylation by LY294002 in the PC3 and MCF10CA1 tumor cell lines similarly failed to result in a significant increase in apoptosis. CONCLUSIONS: Our results show that inhibition of PI3K/PKB signaling by indole-3-carbinol or LY294002 is not directly correlated with induction of apoptosis in several breast or prostate cell lines.

Growth-inhibitory and cell cycle-arresting properties of the rice bran constituent tricin in human-derived breast cancer cells in vitro and in nude mice in vivo.

Tricin, a flavone found in rice bran, inhibits the growth of human-derived malignant MDA-MB-468 breast tumour cells at submicromolar concentrations. As part of the exploration of tricin as a potential cancer chemopreventive agent, we investigated the duration and cell cycle specificity of growth inhibition elicited by tricin in vitro and the effect of tricin on the development of MDA-MB-468 tumours grown in immune-compromised MF-1 mice in vivo. Preincubation of MDA-MB-468 cells with tricin (1-40 microM) for 72 h compromised cell growth after tricin removal, and such irreversibility was not observed in human breast-derived nonmalignant HBL-100 cells. Tricin (>/=5 microM) arrested MDA-MB-468 cells in the G2/M phase of the cell cycle without inducing apoptosis as adjudged by annexin V staining. In nude mice consumption of tricin with the diet (0.2%, w w(-1)) from 1 week prior to MDA-MB-468 cell implantation failed to impede tumour development. Steady-state levels of tricin in plasma, breast tumour tissue and intestinal mucosa, as measured by HPLC, were 0.13 microM and 0.11 and 63 nmol g(-1), respectively. Cells were exposed to tricin (0.11, 1.1 or 11 microM) in vitro for 72 h and then implanted into mice. The volume of tumours in animals bearing cells pre-exposed to 11 microM tricin was less than a third of that in mice with control cells, while tumours from cells incubated with 0.1 or 1.1 microM tricin were indistinguishable from controls. These results suggest that the potent breast tumour cell growth-inhibitory activity of tricin in vitro does not directly translate into activity in the nude mouse bearing the MDA MB-468 tumour. While the results do not support the notion that tricin is a promising candidate for breast cancer chemoprevention, its high levels in the gastrointestinal tract after dietary intake render exploration of its ability to prevent colorectal carcinogenesis propitious.

Growth-inhibitory effects of the chemopreventive agent indole-3-carbinol are increased in combination with the polyamine putrescine in the SW480 colon tumour cell line.

BACKGROUND: Many tumours undergo disregulation of polyamine homeostasis and upregulation of ornithine decarboxylase (ODC) activity, which can promote carcinogenesis. In animal models of colon carcinogenesis, inhibition of ODC activity by difluoromethylornithine (DFMO) has been shown to reduce the number and size of colon adenomas and carcinomas. Indole-3-carbinol (I3C) has shown promising chemopreventive activity against a range of human tumour cell types, but little is known about the effect of this agent on colon cell lines. Here, we investigated whether inhibition of ODC by I3C could contribute to a chemopreventive effect in colon cell lines. METHODS: Cell cycle progression and induction of apoptosis were assessed by flow cytometry. Ornithine decarboxylase activity was determined by liberation of CO2 from 14C-labelled substrate, and polyamine levels were measured by HPLC. RESULTS: I3C inhibited proliferation of the human colon tumour cell lines HT29 and SW480, and of the normal tissue-derived HCEC line, and at higher concentrations induced apoptosis in SW480 cells. The agent also caused a decrease in ODC activity in a dose-dependent manner. While administration of exogenous putrescine reversed the growth-inhibitory effect of DFMO, it did not reverse the growth-inhibition following an I3C treatment, and in the case of the SW480 cell line, the effect was actually enhanced. In this cell line, combination treatment caused a slight increase in the proportion of cells in the G2/M phase of the cell cycle, and increased the proportion of cells undergoing necrosis, but did not predispose cells to apoptosis. Indole-3-carbinol also caused an increase in intracellular spermine levels, which was not modulated by putrescine co-administration. CONCLUSION: While indole-3-carbinol decreased ornithine decarboxylase activity in the colon cell lines, it appears unlikely that this constitutes a major mechanism by which the agent exerts its antiproliferative effect, although accumulation of spermine may cause cytotoxicity and contribute to cell death. The precise mechanism by which putrescine enhances the growth inhibitory effect of the agent remains to be elucidated, but does result in cells undergoing necrosis, possibly following accumulation in the G2/M phase of the cell cycle.