Age-related difference in susceptibility of ApcMin/+ mice towards the chemopreventive efficacy of dietary aspirin and curcumin

The nonsteroidal anti-inflammatory drug aspirin and the spice curcumin retard adenoma formation when administered long-term to ApcMin/+ mice, a model of human familial adenomatous polyposis coli. Both agents interfere with cyclooxygenase activity. When aspirin is administered to ApcMin/+ mice only postweaning, but not before, it is inefficacious, while curcumin given postweaning is active. Here the hypothesis was tested that dietary aspirin (0.05%) or curcumin (0.2%) prevent or delay adenoma formation in offsprings when administered to ApcMin/+ mothers and up to the end of weaning, but not afterwards. Whereas curcumin was without effect when administered in this way, aspirin reduced numbers of intestinal adenomas by 21%. When aspirin given up to the end of weaning was combined with curcumin administered from the end of weaning for the rest of the animals' lifetime, intestinal adenoma numbers were reduced by 38%. The combination was not superior to intervention postweaning with curcumin alone. These results show that aspirin exerts chemopreventive activity in the ApcMin/+ mouse during tumour initiation/early promotion, while curcumin is efficacious when given at a later stage of carcinogenic progression. Thus, the results suggest that in this mouse model aspirin and curcumin act during different ‘windows’ of neoplastic development

Effect of Sulindac Sulfide on Metallohydrolases in the Human Colon Cancer Cell Line HT-29

Matrix metalloproteinase 7 (MMP7), a metallohydrolase involved in the development of several cancers, is downregulated in the ApcMin/+ colon cancer mouse model following sulindac treatment. To determine whether this effect is relevant to the human condition, HT-29 human colon cancer cells were treated with sulindac and its metabolites, and compared to results obtained from in vivo mouse studies. The expression of MMP7 was monitored. The results demonstrated that sulindac sulfide effectively downregulated both MMP7 expression and activity. Furthermore, activity-based proteomics demonstrated that sulindac sulfide dramatically decreased the activity of leukotriene A4 hydrolase in HT-29 cells as reflected by a decrease in the level of its product, leukotriene B4. This study demonstrates that the effect of sulindac treatment in a mouse model of colon cancer may be relevant to the human counterpart and highlights the effect of sulindac treatment on metallohydrolases

Determination of an optimal dosing regimen for aspirin chemoprevention of 1,2-dimethylhydrazine-induced colon tumours in rats

In order to establish an optimal timing and duration of aspirin treatment in the chemoprevention of 1,2-dimethylhydrazine (DMH)-induced colon cancer in rats, colon tumours were induced using an established protocol and aspirin was given in the diet at 500 p.p.m. during various stages of colon carcinogenesis. Results indicate that only aspirin treatment throughout the entire carcinogenic period significantly reduced tumour incidence and volume whereas intermittent aspirin dosing increased tumour number and/or volume, suggesting that aspirin must be used for an extended period in order to gain any chemopreventive benefit. © 1999 Cancer Research Campaig

Bortezomib in combination with celecoxib in patients with advanced solid tumors: a phase I trial

<p>Abstract</p> <p>Background</p> <p>COX-2 inhibitors, such as celecoxib, and ubiquitin-proteasome pathway inhibitors, such as bortezomib, can down-regulate NF-κB, a transcription factor implicated in tumor growth. The objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of bortezomib in combination with celecoxib in patients with advanced solid tumors.</p> <p>Methods</p> <p>Patients received escalating doses of bortezomib either on a weekly schedule (days 1, 8, 15, 22, and 29 repeated every 42 days) or on a twice-weekly administration schedule (days 1, 4, 8, and 11 repeated every 21 days), in combination with escalating doses of celecoxib twice daily throughout the study period from 200 mg to 400 mg twice daily.</p> <p>Results</p> <p>No dose-limiting toxicity was observed during the study period. Two patients had stable disease lasting for four and five months each, and sixteen patients developed progressive disease.</p> <p>Conclusion</p> <p>The combination of bortezomib and celecoxib was well tolerated, without dose limiting toxicities observed throughout the dosing ranges tested, and will be studied further at the highest dose levels investigated.</p> <p>Trial registration number</p> <p>NCT00290680.</p

Multifocality and multicentricity are not contraindications for sentinel lymph node biopsy in breast cancer surgery

BACKGROUND: After the availability of the results of validation studies, the sentinel lymph node biopsy (SLNB) has replaced routine axillary dissection (AD) as the new standard of care in early unifocal breast cancers. Multifocal (MF) and multicentric (MC) tumors have been considered a contraindication for this technique due to the possible incidence of a higher false-negative rate. This prospective study evaluates the lymphatic drainage from different tumoral foci of the breast and assesses the accuracy of SLNB in MF-MC breast cancer. PATIENTS AND METHODS: Patients with preoperative diagnosis of MF or MC infiltrating and clinically node-negative (cN0) breast carcinoma were enrolled in this study. Two consecutive groups of patients underwent SLN mapping using a different site of injection of the radioisotope tracer: a) "2ID" Group received two intradermal (ID) injections over the site of the two dominant neoplastic nodules. A lymphoscintigraphic study was performed after each injection to evaluate the route of lymphatic spreading from different sites of the breast. b) "A" Group had periareolar (A) injection followed by a conventional lymphoscintigraphy. At surgery, both radioguided SLNB (with frozen section exam) and subsequent AD were planned, regardless the SLN status. RESULTS: A total 31 patients with MF (n = 12) or MC (n = 19) invasive, cN0 cancer of the breast fulfil the selection criteria. In 2 ID Group (n = 15) the lymphoscintigraphic study showed the lymphatic pathways from two different sites of the breast which converged into one major lymphatic trunk affering to the same SLN(s) in 14 (93.3%) cases. In one (6.7%) MC cancer two different pathways were found, each of them affering to a different SLN. In A Group (n = 16) lymphoscintigraphy showed one (93.7%) or two (6.3%) lymphatic channels, each connecting areola with one or more SLN(s). Identification rate of SLN was 100% in both Groups. Accuracy of frozen section exam on SLN was 96.8% (1 case of micrometastasis was missed). SLN was positive in 13 (41.9%) of 31 patients, including 4 cases (30.7%) of micrometastasis. In 7 of 13 (53.8%) patients the SLN was the only site of axillary metastasis. SLNB accuracy was 96.8% (30 of 31), sensitivity 92.8 (13 of 14), and false-negative rate 7.1% (1 of 14). Since the case of skip metastasis was identified by the surgeon intraoperatively, it would have been no impact in the clinical practice. CONCLUSION: Our lymphoscintigraphic study shows that axillary SLN represents the whole breast regardless of tumor location within the parenchyma. The high accuracy of SLNB in MF and MC breast cancer demonstrates, according with the results of other series published in the literature, that both MF and MC tumors do not represent a contraindication for SLNB anymore

Aspirin induces cell death and caspase-dependent phosphatidylserine externalization in HT-29 human colon adenocarcinoma cells

The induction of cell death by aspirin was analysed in HT-29 colon carcinoma cells. Aspirin induced two hallmarks of apoptosis: nuclear chromatin condensation and increase in phosphatidylserine externalization. However, aspirin did not induce either oligonucleosomal fragmentation of DNA, decrease in DNA content or nuclear fragmentation. The effect of aspirin on Annexin V binding was inhibited by the caspase inhibitor Z-VAD.fmk, indicating the involvement of caspases in the apoptotic action of aspirin. However, aspirin did not induce proteolysis of PARP, suggesting that aspirin does not increase nuclear caspase 3-like activity in HT-29 cells. This finding may be related with the ‘atypical’ features of aspirin-induced apoptosis in HT-29 cells. © 1999 Cancer Research Campaig

Evaluation of the cancer chemopreventive efficacy of rice bran in genetic mouse models of breast, prostate and intestinal carcinogenesis

Brown rice is a staple dietary constituent in Asia, whereas rice consumed in the Western world is generally white, obtained from brown rice by removal of the bran. We tested the hypothesis that rice bran interferes with development of tumours in TAg, TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) or ApcMin mice, genetic models of mammary, prostate and intestinal carcinogenesis, respectively. Mice received rice bran (30%) in AIN-93G diet throughout their post-weaning lifespan. In TAg and TRAMP mice, rice bran did not affect carcinoma development. In TRAMP or wild-type C57Bl6/J mice, dietary rice bran increased kidney weight by 18 and 20%, respectively. Consumption of rice bran reduced numbers of intestinal adenomas in ApcMin mice by 51% (P<0.01), compared to mice on control diet. In parallel, dietary rice bran decreased intestinal haemorrhage in these mice, as reflected by increased haematocrit. At 10% in the diet, rice bran did not significantly retard ApcMin adenoma development. Likewise, low-fibre rice bran (30% in the diet) did not affect intestinal carcinogenesis, suggesting that the fibrous constituents of the bran mediate chemopreventive efficacy. The results suggest that rice bran might be beneficially evaluated as a putative chemopreventive intervention in humans with intestinal polyps

Clinical aspects of sentinel node biopsy

Sentinel lymph node (SLN) biopsy requires validation by a backup axillary dissection in a defined series of cases before becoming standard practice, to establish individual and institutional success rates and the frequency of false negative results. At least 90% success in finding the SLN with no more than 5-10% false negative results is a reasonable goal for surgeons and institutions learning the technique. A combination of isotope and dye to map the SLN is probably superior to either method used alone, yet a wide variety of technical variations in the procedure have produced a striking similarity of results. Most breast cancer patients are suitable for SLN biopsy, and the large majority reported to date has had clinical stage T1-2N0 invasive breast cancers. SLN biopsy will play a growing role in patients having prophylactic mastectomy, and in those with 'high-risk' duct carcinoma in situ, microinvasive cancers, T3 disease, and neoadjuvant chemotherapy. SLN biopsy for the first time makes enhanced pathologic analysis of lymph nodes logistically feasible, at once allowing greater staging accuracy and less morbidity than standard methods. Retrospective data suggest that micrometastases identified in this way are prognostically significant, and prospective clinical trials now accruing promise a definitive answer to this issue