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Biomedical subjects

G P Young

Publications and source records attributed to G P Young.

At least 19 recordsLinked to original sources
PubMed2006

Screening for colorectal cancer by faecal occult blood test: why people choose to refuse.

To better understand the personal barriers that limit participation in faecal occult blood test (FOBT) screening for colorectal cancer, non-participants from a recent screening initiative were sent detailed questionnaires, defining their reasons for not participating, as well as how to make screening more attractive. The important barrier was procrastination. The type of FOBT kit offered influenced the reasons for not participating. Convenient FOBT and greater general practitioner involvement may be important for optimizing community acceptance of FOBT-based screening.

Aged↗
PubMed2005

Treatment and survival from colorectal cancer: the experience of patients at South Australian teaching hospitals between 1980 and 2002.

AIMS: To evaluate trends in colorectal cancer survival and treatment at South Australian teaching hospitals and degree of adherence to treatment guidelines which recommend adjuvant chemotherapy for Dukes' C colon cancers and combined chemotherapy and radiotherapy for high-risk rectal cancers. MATERIALS AND METHODS: Trends in disease specific survival and primary treatment were analysed, and comparisons drawn between diagnostic epochs, using cancer registry data from South Australian teaching hospitals. Statistical methods included univariate and multivariable disease specific survival analyses. RESULTS: Five-year survival increased from 48% in 1980-1986 to 56% in 1995-2002. Largest gains were for stage C, where survivals were higher when chemotherapy was part of the primary treatment. By comparison, gains in 1-year survival were largest for stage D. Chemotherapy was provided for 4% of patients with colorectal cancers in 1980-1986, increasing to 32% in 1995-2002. Among stage C cases below 70 years at diagnosis, the proportion having chemotherapy increased to 83% in 1995-2002. The most common chemotherapy was fluorouracil (5FU) as a single agent in 1980-1986 and 5FU with leucovorin in 1995-2002. As expected, radiotherapy was used more frequently for rectal than colon cancers, and particularly for stage C. Among stage C rectal cases below 70 years, the proportion having radiotherapy increased from 10% in 1980-1986 to 57% in 1995-2002. Approximately 93% of colorectal cancers were treated surgically. Patients not treated surgically tended to be aged 80 years or more and to present with distant metastases. CONCLUSIONS: Trends in chemotherapy and radiotherapy accord with evidence-based recommendations. There have been reassuring gains in survivals after adjusting for stage, grade and other prognostic indicators. The data show survival gains and treatment patterns that individual hospitals can use as benchmarks when evaluating their own experience.

Aged↗
PubMed2005

Interval faecal occult blood testing in a colonoscopy based screening programme detects additional pathology.

BACKGROUND: Colonoscopic based surveillance is recommended for patients at increased risk of colorectal cancer. The appropriate interval between surveillance colonoscopies remains in debate, as is the "miss rate" for colorectal cancer within such screening programmes. AIMS: The main aim of this study was to determine whether a one-off interval faecal occult blood test (FOBT) facilitates the detection of significant neoplasia within a colonoscopic based surveillance programme. Secondary aims were to determine if invitees were interested in participating in interval screening, and to determine whether interval lesions were missed or whether they developed rapidly since the previous colonoscopy PATIENTS: Patients enrolled in a colonoscopic based screening programme due to a personal history of colorectal neoplasia or a significant family history. METHODS: Patients within the screening programme were invited to perform an immunochemical FOBT (Inform). A positive result was followed by colonoscopy; significant neoplasia was defined as colorectal cancer, adenomas either > or =10 mm or with a villous component, high grade dysplasia, or multiplicity (>/=3 adenomas). Participation rates were determined for age, sex, and socioeconomic subgroups. Colonoscopy recall databases were examined to determine the interval between previous colonoscopy and FOBT offer, and correlations between lesion characteristics and interval time were determined. RESULTS: A total of 785 of 1641 patients invited (47.8%) completed an Inform kit. A positive result was recorded for 57 (7.3%). Fifty two of the 57 test positive patients completed colonoscopy; 14 (1.8% of those completing the FOBT) had a significant neoplastic lesion. These consisted of six colorectal cancers and eight significant adenomas. CONCLUSIONS: A one off immunochemical faecal occult blood test within a colonoscopy based surveillance programme had a participation rate of nearly 50% and appeared to detect additional pathology, especially in patients with a past history of colonic neoplasia.

Adult↗
PubMed2003

A sensitive guaiac faecal occult blood test is less useful than an immunochemical test for colorectal cancer screening in a Chinese population.

BACKGROUND: Colorectal cancer screening by guaiac faecal occult blood test has been shown to reduce the incidence and mortality of colorectal cancer in Western populations. The optimal faecal occult blood test, whether guaiac or immunochemical, for colorectal cancer screening in the Chinese population remains to be defined. AIM: To compare the performance characteristics of a sensitive guaiac-based faecal occult blood test (Hemoccult SENSA) and an immunochemical faecal occult blood test (FlexSure OBT) in a Chinese population referred for colonoscopy. METHODS: One hundred and thirty-five consecutive patients who were referred for colonoscopy and who met the study inclusion criteria took samples for the two faecal occult blood tests simultaneously from three successive stool specimens, with no dietary restrictions. All tests were developed and interpreted by a single experienced technician who was blind to the clinical diagnosis. The sensitivity, specificity and positive predictive value for the detection of colorectal adenomas and cancers were estimated for the two tests. RESULTS: The sensitivity, specificity and positive predictive value for the detection of significant colorectal neoplasia (adenomas > or = 1.0 cm and cancers) were 91%, 70% and 18% for Hemoccult SENSA and 82%, 94% and 47% for FlexSure OBT. The specificity and positive predictive value were significantly higher for FlexSure OBT than for Hemoccult SENSA (P < 0.001 and P = 0.016, respectively). Combining the positive results from both faecal occult blood tests did not improve the accuracy. CONCLUSION: The positive predictive value of the immunochemical faecal occult blood test for the detection of significant colorectal neoplasia was 29% better than that of the sensitive guaiac-based test. This may relate to the Chinese diet and requires further study. The poor specificity of the sensitive guaiac-based test, without dietary restriction, makes it less useful for colorectal cancer screening in a Chinese population.

Adult↗
PubMed2003

A randomised trial of the impact of new faecal haemoglobin test technologies on population participation in screening for colorectal cancer.

OBJECTIVES: To investigate the effect on participation in colorectal cancer screening of testing for blood products in faeces using technologies that remove dietary restrictions (i.e. immunochemical tests) and simplify faecal sampling (i.e. tests that use brush sampling). METHODS SETTING: Urban residents (n=1818) of Adelaide, Australia, aged between 50 and 69 years, randomly selected from the electoral roll. DESIGN: Three randomised cohorts of 606 invitees were offered a screening test by mail in 2001. The Hemoccult SENSA and FlexSure OBT cohorts were instructed to sample three stools using a spatula while the InSureTM cohort sampled two stools using a brush. The Hemoccult SENSA cohort was asked to restrict certain (high-peroxidase) foods and drugs. MAIN OUTCOME MEASURES: Participation (i.e. return of completed sample kits within 12 weeks) and generalised linear modelling (GLM) of relationships between participation, test technologies and demographic variables. RESULTS: Participation was 23.4%, 30.5% and 39.6% for the Hemoccult, FlexSure and InSure cohorts, respectively (chi(2)=37.1, p<0.00001). GLM demonstrated that participation was increased by 28% by removal of restrictions (p=0.01) and by 30% by simplification of sampling (p=0.001); both together increased participation by 66% (p<0.001). The differences in participation between tests occurred in the first three weeks. Socio-economic status, gender or age did not significantly influence technology-based improvements in participation. CONCLUSIONS: The brush-sampling faecal immunochemical test for haemoglobin (InSure) achieves the best participation rates by simplifying sampling and removing the need for restrictions of diet and drugs. Because participation in screening is vital to detection, this new technology should contribute to better detection of neoplasia at the population level.

Aged↗
PubMed2003

Prescreening evaluation of a brush-based faecal immunochemical test for haemoglobin.

OBJECTIVES: To undertake a prescreening evaluation of a new brush-based faecal immunochemical test for haemoglobin, relative to a traditional spatula-sampling immunochemical test. METHODS SETTING: Patients aged between 24 and 90 years, scheduled to undergo diagnostic colonoscopy in two major urban hospitals, for a range of clinical indications. DESIGN: Patients sampled three stools using a spatula for the reference FlexSure OBT test and two stools using a brush for the InSure test; order of sampling was randomised. Faecal haemoglobin was quantified by a modified InSure in a subset of patients to determine whether brush-sampling allowed discrimination between groups. MAIN OUTCOME MEASURES: Sensitivity for cancer or adenoma; false-positive rate in normals. Faecal haemoglobin levels. Preference for sampling method. RESULTS: InSure and FlexSure OBT did not differ in their sensitivities for cancer (27/36, 75% vs 29/36, 80.5%, respectively), adenomas >or= 10 mm (12/29, 41.4% vs 13/29, 44.8%) or adenomas <10 mm (each 8/56, 14.3%). Likewise, false-positive rates in normals were similar: 4/179 (2.2%) and 5/179 (2.8%) respectively (specificities of 97.8% and 97.2%, respectively). Levels of faecal haemoglobin were highest in those with cancers; those with adenomas had intermediate levels which were also significantly higher than those in normals. The brush sampling method was preferred by 38/46 (82.6%), while 4/46 (8.7%) preferred the spatula (p<0.00001). CONCLUSIONS: InSure is as sensitive and specific as FlexSure OBT for faecal haemoglobin. The novel stool-sampling method of InSure allows discrimination between normals and classes of neoplasia, and is highly preferred. The brush-sampling faecal immunochemical test InSure should now be evaluated in a screening population.

Adenoma↗
PubMed2002

Effects of resistant starch and nonstarch polysaccharides on colonic luminal environment and genotoxin-induced apoptosis in the rat.

Fermentation of polysaccharides in the colon seems likely to regulate tumorigenesis but the mechanisms are unclear. A possible mechanism may be through facilitation of the acute apoptotic response to genotoxin-induced DNA damage. This study evaluated the effects of selected dietary polysaccharides, resistant starch (supplied as Hi-maize) and nonstarch polysaccharides (supplied as wheat bran and cellulose) on certain biological events relevant to protection against colon cancer (fecal bulk, pH, butyrate and apoptosis). Male Sprague-Dawley rats were fed the different experimental diets for a period of 4 weeks, after which a single azoxymethane injection was given to induce DNA damage; 6 h later the acute apoptotic response was measured. Other measures included short chain fatty acid (SCFA) levels, fecal bulk and pH. All wheat bran treatments significantly (P < 0.05) enhanced carcinogen-induced apoptosis in the distal colon, increased fecal bulk and butyrate levels and reduced fecal pH, when compared with rats fed NF or Cellulose diets. Total SCFA (P < 0.001, r = 0.496) and butyrate levels (P < 0.001, r = 0.353) in the feces correlated positively with the acute apoptotic response in distal colonic crypts. Resistant starch supplementation by this modest amount did not enhance carcinogen-induced apoptosis. While it did significantly increase bulk, SCFA and butyrate levels and lower pH, the magnitude of these effects was not as great as with wheat bran. These findings indicate that wheat bran is the most effective regulator of these biological events of relevance to protection against colon cancer. Assuming that the acute apoptotic response to genotoxic carcinogens acts to remove genetically damaged cells that might otherwise form mutated clones that progress to malignancy, we have identified an additional biological mechanism by which dietary polysaccharides provide protection.

Amylose↗
PubMed2002

The colonic response to genotoxic carcinogens in the rat: regulation by dietary fibre.

The apoptotic response to DNA damage appears to be an innate biological mechanism for protection against tumourigenesis. It is possible that agents that protect against colorectal cancer act by enhancing the apoptotic deletion of cells suffering DNA damage, with consequent removal of those with tumourigenic mutations. We examined the acute apoptotic response to genotoxic carcinogens ("AARGC") in colonic epithelium and the possibility that dietary fibres of different fermentability might regulate AARGC. To fully define the time-course and nature of AARGC in response to the carcinogen azoxymethane (AOM), a single injection of AOM (10 mg/kg) was given to rats and apoptosis monitored in the colon by light microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling staining over a 72 h period. Having defined the site and time of maximum response, two groups of eight rats were fed diets containing 10% wheat bran fibre (WB; fermentable) or 10% methylcellulose (MC; poorly fermentable) for 4 weeks. Colonic AARGC was compared by light microscopy; lumenal short chain fatty acids (SCFAs) and pH were measured as indicators of the fermentative environment. AOM-induced AARGC was maximal at 8 h and greater in distal compared with proximal colon. Apoptotic cells were situated predominantly in the lower half of the crypt, with the median at position 9 indicating involvement of daughter as well as stem cells. There was no "second wave" of apoptosis within 72 h as follows irradiation in small intestine. Distal colonic AARGC in rats fed WB was twice that in rats fed MC (P < 0.01). Compared with MC, WB significantly lowered lumenal pH and increased all SCFAs including butyrate, while proliferation did not differ between the fibres. Certainly, dietary fibres can regulate AARGC and further studies are warranted to determine if this biological effect is the way in which dietary factors regulate tumourigenesis. Lumenal generation of butyrate may enhance AARGC as butyrate is proapoptotic in vitro.

Animals↗
PubMed2002

Participation in screening for colorectal cancer based on a faecal occult blood test is improved by endorsement by the primary care practitioner.

OBJECTIVES: To investigate the influence of general practitioner (GP) endorsement on participation in screening for colorectal cancer based on a faecal occult blood test (FOBT). SETTING: South Australian residents (n=2400), in 1999, aged >50 years. METHODS: Random selection of three groups (GP1, GP2, GP3) from two general practices and of one group (ER) from the federal electoral roll; n=600 per group. Without previous communication or publicity, subjects were posted an offer of screening by immunochemical FOBT. The GP1 and ER groups were invited without indication that their GP was involved; GP2 received an invitation indicating support from the practice; and GP3 received an invitation on practice letterhead and signed by a practice partner. A reminder was posted at 6 weeks. Participation was defined as return of correctly completed FOBT sample cards within 12 weeks. RESULTS: Participation rates were: GP1 192/600 (32.0%), GP2 228/600 (38.0%), and GP3 244/600 (40.7%); chi(2)=10.2, p=0.006. Both GP2 and GP3 differed significantly from GP1 (odds ratio (OR) 0.77, 95% confidence interval (95% CI) 0.60 to 0.98 and relative risk (RR)=0.69, 95% CI 0.54 to 0.87 respectively). ER (193/600 (32.2%)) and GP1 were not significantly different. Age but not sex was significantly associated with participation. Overall test positivity rate was 4.6%; five malignancies were found in the 918 who performed FOBT. CONCLUSIONS: Association of a GP of recent contact with a screening offer in the form of a personalised letter of invitation achieves better participation than does the same letter from a centralised screening unit that does not mention the GP. Thus, GP enhanced participation is achievable without their actual involvement. Additional strategies are needed to further improve participation.

Age Factors↗
PubMed2001

Effect of dietary restriction on participation in faecal occult blood test screening for colorectal cancer.

OBJECTIVES: To determine if participation in colorectal cancer screening using faecal occult blood testing (FOBT) is affected by a restrictive diet and if it is associated with certain demographic variables. PARTICIPANTS AND SETTING: 1,203 residents of South Australia aged 50-69 years, with no "currently active bowel disease", randomly selected from a database of people willing to be contacted about unspecified health issues. DESIGN: Randomised controlled trial: participants were offered screening by immunochemical FOBT by mail in 1998. Half were randomly allocated to a group instructed to follow a low-peroxidase diet, as required for guaiac FOBT, while the other group was not so restricted. MAIN OUTCOME MEASURES: Effect of diet restriction on participation (return of correctly completed FOBT sample cards within 15 weeks); time taken to return cards; relationships between participation and demographic variables. RESULTS: Participation rates were 65.9% (no-diet group) and 53.3% (diet group) (difference, 12.6%; 95% CI, 7.1%-18.1%). In the first week, rates of return as a proportion of all tests returned were 13.1% (no-diet) and 1.6% (diet) (difference, 11.5%; 95% CI, 8.6%-14.4%), increasing to 54.3% and 44.5%, respectively, after five weeks (difference, 9.8%; 95% CI, 4.2%-15.4%). Participation was significantly associated with older age (odds ratio, 1.40; 95% CI, 1.10-1.78), but not sex, Index of Social Disadvantage or rural versus urban address. CONCLUSIONS: Dietary restrictions create a barrier to FOBT-based screening for colorectal cancer. The use of immunochemical rather than guaiac FOBT removes this barrier.

Aged↗
PubMed2000

A randomized trial of the effects of early cardiac serum marker availability on reperfusion therapy in patients with acute myocardial infarction: the serial markers, acute myocardial infarction and rapid treatment trial (SMARTT).

OBJECTIVES: The purpose of this study was to assess whether the immediate availability of serum markers would increase the appropriate use of thrombolytic therapy. BACKGROUND: Serum markers such as myoglobin and creatine kinase, MB fraction (CK-MB) are effective in detecting acute myocardial infarction (AMI) in the emergency setting. Appropriate candidates for thrombolytic therapy are not always identified in the emergency department (ED), as 20% to 30% of eligible patients go untreated, representing 10% to 15% of all patients with AMI. Patients presenting with chest pain consistent with acute coronary syndrome were evaluated in the EDs of 12 hospitals throughout North America. METHODS: In this randomized, controlled clinical trial, physicians received either the immediate myoglobin/CK-MB results at 0 and 1 h after enrollment (stat) or conventional reporting of myoglobin/CK-MB 3 h or more after hospital admission (control). The primary end point was the comparison of the proportion of patients within the stat group versus control group who received appropriate thrombolytic therapy. Secondary end points included the emergent use of any reperfusion treatment in both groups, initial hospital disposition of patients (coronary care unit, monitor or nonmonitor beds) and the proportion of patients appropriately discharged from the ED. RESULTS: Of 6,352 patients enrolled, 814 (12.8%) were diagnosed as having AMI. For patients having AMI, there were no statistically significant differences in the proportion of patients treated with thrombolytic therapy between the stat and control groups (15.1% vs. 17.1%, p = 0.45). When only patients with ST segment elevation on their initial electrocardiogram were compared, there were still no significant differences between the groups. Also, there was no difference in the hospital placement of patients in critical care and non- critical care beds. The availability of early markers was associated with more hospital admissions as compared to the control group, as the number of patients discharged from the ED was decreased in the stat versus control groups (28.4% vs. 31.5%, p = 0.023). CONCLUSIONS: The availability of 0- and 1-h myoglobin and CK-MB results after ED evaluation had no effect on the use of thrombolytic therapy for patients presenting with AMI, and it slightly increased the number of patients admitted to the hospital who had no evidence of acute myocardial necrosis.

Biomarkers↗
PubMed2000

Amylase-resistant starch plus oral rehydration solution for cholera.

BACKGROUND: Although standard glucose-based oral rehydration therapy corrects the dehydration caused by cholera, it does not reduce the diarrhea. Short-chain fatty acids, which are produced in the colon from nonabsorbed carbohydrates, enhance sodium absorption. We conducted a study to determine the effects of an orally administered, nonabsorbed starch (i.e., one resistant to digestion by amylase) on fecal fluid loss and the duration of diarrhea in patients with cholera. METHODS: We randomly assigned 48 adolescents and adults with cholera to treatment with standard oral rehydration therapy (16 patients), standard therapy and 50 g of rice flour per liter of oral rehydration solution (16 patients), or standard therapy and 50 g of high-amylose maize starch, an amylase-resistant starch, per liter of oral rehydration solution (16 patients). The primary end points were fecal weight (for every 12-hour period during the first 48 hours after enrollment) and the length of time to the first formed stool. RESULTS: The mean (+/-SD) fecal weights in the periods 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours after enrollment were significantly lower in the resistant-starch group (2206+/-1158 g, 1810+/-1018 g, and 985+/-668 g) than in the standard-therapy group (3251+/-766 g, 2621+/-1149 g, and 2498+/-1080 g; P=0.01, P= 0.04, and P=0.001, respectively). From 36 to 48 hours after enrollment, fecal weight was also significantly lower with the resistant-starch therapy than with the rice-flour therapy (985+/-668 g vs. 1790+/-866 g, P=0.01). The mean duration of diarrhea was significantly shorter with the resistant-starch therapy (56.7+/-18.6 hours) than with standard therapy alone (90.9+/-29.8 hours, P=0.001) or the rice-flour therapy (70.8+/-20.2 hours, P=0.05). Fecal excretion of starch was higher with the resistant-starch therapy (32.6+/-30.4) than with the standard therapy (11.7+/-4.1 g, P=0.002) or the rice-flour therapy (15.1+/-8.4 g, P=0.01). CONCLUSIONS: The addition of a resistant starch to oral rehydration solution reduces fecal fluid loss and shortens the duration of diarrhea in adolescents and adults with cholera.

Adolescent↗
PubMed2000

Folate deficiency diminishes the occurrence of aberrant crypt foci in the rat colon but does not alter global DNA methylation status.

BACKGROUND AND AIMS: It has been suggested that a diminished folate status may enhance colorectal carcinogenesis by causing DNA hypomethylation. The aims of the present study were to assess the impact of different levels of folate depletion on azoxymethane (AOM)-induced aberrant crypt foci (ACF) formation and DNA hypomethylation in the colon of male Sprague-Dawley rats. METHODS: Rats, aged 4 weeks, were divided into four groups and were fed semipurified diets either containing adequate folate (control), devoid of folate (FD) or FD + 1% succinylsulfathiazole before AOM treatment (FD1) or during the last 4 weeks of the study (FD2). At 8 weeks of age, all animals received subcutaneous injections of AOM once weekly for 3 weeks at a dose rate of 15 mg/kg bodyweight. Animals were necropsied 6 weeks after the last AOM injection and the ACF were visualized under light microscopy in formalin-fixed, methylene blue-stained colons. RESULTS: Blood folate concentrations were significantly depleted (P < 0.001) in the treatment groups consuming folate deplete diets, with the FD2 treatment group having significantly lower folate levels compared with all other groups. Higher plasma homocysteine concentrations (P < 0.001) were observed in the groups that exhibited diminished blood folate levels. There were no significant differences in global DNA methylation in the liver or colonic mucosa between the four groups, despite some groups exhibiting marked folate depletion. Animals with the most severe folate deficiency (FD2) had a lower final bodyweight and had significantly fewer ACF in their colon (P < 0.05) compared with control animals. Total (mean +/- SEM) ACF counts were as follows: control 286+/-24; FD 290+/-25; FD1 218+/-32; and FD2 205+/-27. CONCLUSIONS: In this model, folate deficiency diminished the occurrence of ACF but did not alter global DNA methylation status in the colon.

Animals↗
PubMed2000

Intracellular zinc depletion induces caspase activation and p21 Waf1/Cip1 cleavage in human epithelial cell lines.

To better understand the mechanisms by which zinc deficiency induces epithelial cell death, studies were done of the effects of intracellular zinc depletion induced by the zinc chelator TPEN on apoptosis-related events in human malignant epithelial cell lines LIM1215 (colonic), NCI-H292 (bronchial), and A549 (alveolar type II). In TPEN-treated cells, depletion of zinc was followed by activation of caspase-3 (as demonstrated by enzymatic assay and Western blotting), DNA fragmentation, and morphologic changes. Increase in caspase-3 activity began 12 h after addition of TPEN, suggesting that zinc may suppress a step just before the activation of this caspase. Caspase-6, a mediator of caspase-3 processing, also increased, but later than caspase-3. Effects of TPEN on apoptosis were completely prevented by exogenous ZnSO4 and partially prevented by peptide caspase inhibitors. A critical substrate of caspase-3 may be the cell cycle regulator p21Waf1/Cip1, which was rapidly cleaved in TPEN-treated cells to a 15-kDa fragment before further degradation.

Apoptosis↗
PubMed2000

Involvement of p21(Waf1/Cip1) and its cleavage by DEVD-caspase during apoptosis of colorectal cancer cells induced by butyrate.

Butyrate, a short chain fatty acid produced in the colon, induces apoptosis in cancer cell lines by a sequential process involving inhibition of histone deacetylase, de novo protein synthesis and activation of DEVD-caspase, a major effector of apoptotic DNA fragmentation and membrane blebbing. We now show, in LIM 1215 colorectal cancer cells, that butyrate, in addition to activating DEVD-caspase and inducing apoptosis, also increases expression and cleavage of the universal cyclin-dependent kinase inhibitor p21(Waf1/Cip1) and leads to hypo-phosphorylation of retinoblastoma protein. Accompanying these molecular changes was a progressive loss of G(0)/G(1) and S phase cells. Expression of p21 had similar kinetics to that of the essential protein required for DEVD-caspase activation, indicating parallel effects of butyrate on anti-apoptotic and pro-apoptotic mechanisms. LIM 1215 cells, which were resistant to butyrate-induced apoptosis, were selected by three cycles of exposure to butyrate and removal of floating apoptotic cells. These cells showed markedly enhanced p21 expression and were in cell cycle arrest as determined by flow cytometry. On the other hand, subsequent culture of these cells for 2-3 days in the absence of butyrate resulted in down-regulation of p21 and restoration of sensitivity to apoptosis by butyrate. Western blots of butyrate-treated cells undergoing apoptosis consistently demonstrated a 15 kDa band (p15) that was not present in control cultures. This band became apparent immediately after the onset of DEVD-caspase activation, was enriched in the floating apoptotic cell population when compared with the adherent, non-apoptotic cells and was absent in butyrate-resistant cells lacking DEVD-caspase activity. Peptide caspase inhibitors partially blocked appearance of p15. Here we show, for the first time, that p21 is a target of effector caspases in colorectal cancer cells and that the resistance to butyrate-induced apoptosis is characterized by failure of p21 cleavage.

Apoptosis↗