Oncogenes, growth factors, and prognostic indicators in colorectal cancer.
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Biomedical subjects
Publications and source records attributed to S Rowley.
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Increased arachidonic acid concentrations in experimental rodent colonic cancer have been described recently. In humans, a reduced erythrocyte stearic acid to oleic acid ratio has been reported in patients with colorectal cancer and it has been proposed that similar changes exist in the cancer tissue. The long chain fatty acids in the cancers of 15 patients with colorectal cancer were measured and compared with values in the unaffected mucosa. The values were expressed as mean (SD) mg fatty acid/g tissue and compared by analysis of variance. In the cancer tissue arachidonic acid was increased (0.703 (0.109) mg/g v 0.603 (0.127) mg/g, p less than 0.05) as was docosahexaenoic acid (0.211 (0.066) mg/g v 0.148 (0.039) mg/g, p less than 0.001). In contrast, the stearic acid to oleic acid ratio in the cancer tissue was increased rather than decreased, as previously suggested (0.36 (0.05) v 0.29 (0.7), p less than 0.01). Increased arachidonic acid and docosahexaenoic acid concentrations may be related to reduced lipid peroxidation, which is a feature of rapidly growing cells. Alternatively, the increased arachidonic acid values could be due to enhanced desaturase activity upon linoleic and linolenic acid, leading perhaps to increased formation of prostaglandins and other lipoxygenase products.
The expression of the c-myc protein product (p62 c-myc) and deoxyribonucleic acid (DNA) ploidy status was determined by a flow cytometric technique in 83 patients with colorectal cancer followed up for a median of 30 months (range 6-60 months). The OM-11-906 antibody, used to detect p62 c-myc, revealed a 62 kDa and 45 kDa band on Western blots in tumours. Correlation of quantitative dot blotting of tumour mRNA to flow cytometric p62 c-myc expression was good (r = 0.87, P less than 0.01). Levels of p62 c-myc varied in colorectal cancer and low levels (less than 20 fluorescein units) correlated with improved survival (log rank chi 2 = 4.69, df = 1, P = 0.03), and this was a better prognostic index than DNA ploidy (log rank analysis chi 2 = 2.38, df = 1, P less than 0.1). Although expression of the c-myc gene was found, using the OM-11-906 antibody, to be a prognostic feature in colorectal cancer, these and other results need to be interpreted with caution given the presence of two protein bands by Western blotting.
Seventy-five nude mice received subcutaneous inoculation with 1 X 10(7) cells of the human colonic cancer cell lines COLO-320 or HT-29. Tumour growth was assessed over 4 weeks in animals given one of three iso-caloric diets; standard diet, high saturated fat (20% coconut) diet and high n-3 fat (20% Maxepa fish oil) diet. The n-3 diet produced significant tumour growth reduction compared to the other diets for COLO-320 at 3 to 4 weeks (P less than 0.05 at least) and similarly for HT-29 at 4 weeks (P less than 0.05). Significant incorporation of n-3 fatty acids occurred in red cell membranes, adipose tissue and both neutral lipid and phospholipid fractions of tumour lipids in animals fed Maxepa (P less than 0.01 at least). This was accompanied by reduction of linoleic acid and arachidonic acid in these tissues (P less than 0.01 at least) but was most marked in the metabolically labile phospholipid fraction. There was high mitotic activity in the tumours from all the groups but there was no difference according to diet.
We studied density-gradient separation of autologous bone marrow grafts in preparation for ex vivo 4-hydroperoxy-cyclophosphamide (4-HC) purging. A two-step procedure of buffy coat isolation followed by Ficoll-diatrizoate separation was used. Buffy-coat cells were isolated primarily either using the COBE 2991 Blood Cell Processor or Haemonetics 30 Cell Separator. All density-gradient separations were performed using the COBE 2991. The nucleated cell recoveries after buffy-coat isolation were 44.3 +/- 10.4% and 85.1 +/- 10.5% (+/- standard deviation, P less than 0.001) for the Haemonetics 30 and COBE 2991 isolated grafts, respectively. The final nucleated cell recoveries after density-gradient separation for these two buffy-coat techniques were 24.2 +/- 10.1% and 29.5 +/- 14.7% (p = 0.30). Compared to manual density-gradient separation, the techniques using the COBE 2991 recovered slightly higher numbers of nucleated cells and CFU-GM. The red blood cell concentration of the 4-HC incubation mixture was 1.0 +/- 0.6% and the CFU-GM survival after treatment was 2.4 +/- 2.6%. The variability in CFU-GM survival after 4-HC incubation of the density-gradient separated grafts appears less than previous experience treating buffy-coat cells. Density-gradient separation of autologous bone marrow appears to provide a more uniform treatment with 4-HC and may improve the clinical transplant course of the autograft recipient.
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A variety of effective nonsurgical forms of treating bile duct stones have emerged to challenge the traditional role of surgery. Four distinct philosophies have evolved upon which to base treatment: the partisan, supermarket, combination, and deductive philosophies. Adopting the latter, it is argued that surgery remains the gold standard for the great majority of patients. Surgery should, however, give way to non-operative forms of treatment in those who are at high surgical risk because of concomitant medical problems, acute cholangitis and severe gallstone pancreatitis. These newer treatments should increase the proportion of symptomatic patients amenable to treatment.
A simultaneous flow cytometric assay of the nuclear expressed protein product of the c-myc oncogene p62 and deoxyribonucleic acid (DNA) ploidy in archival paraffin-embedded tumor material was undertaken in 179 patients with colorectal cancer, followed for up to 9 years. DNA ploidy showed a survival advantage for diploid tumors (chi 2(1) = 5.39, p = 0.020) and could be used to further divide patients with Dukes' A tumors (chi 2(1) = 4.87, p = 0.027) and Dukes' C tumors (chi 2(1) = 5.33, p = 0.021). By dividing patients into 2 levels of tumor expression of p62 c-myc, there was a trend for improved survival in patients with low expression (chi 2(1) = 3.65, p = 0.056). A combination of ploidy status and p62 c-myc expression improved upon survival prediction by ploidy alone in providing 3 groups (chi 2(2) = 7.86, p = 0.0197). While these results do not suggest a replacement for the Dukes' staging for prognosis (chi 2(3) = 33.82, p less than 0.00001), they strongly support the concept that enhanced expression of c-myc oncogene is associated with the progression of colorectal cancer.
Ninety nude mice were inoculated subcutaneously with 1 x 10(7) cells of the human colonic cancer cell lines, SW-620 and LS174T. Tumour growth was assessed weekly for three weeks whilst the animals were receiving one of three diets: control (4.6% fat), coconut (20% fat, saturated fatty acids) and Maxepa (20% fat; n-3 fatty acids). At the end of the study SW-620 tumour weights (mean +/- SD, gm) were: control = 0.38 +/- 0.22, coconut = 0.43 +/- 0.31, Maxepa 0.20 +/- 0.16; the LS174T tumour weights were control = 1.33 +/- 1.27, coconut = 0.47 +/- 0.74, Maxepa = 0.38 +/- 0.56 (p less than 0.001, analysis of covariance). The Maxepa diet produced significant retardation in tumour growth (p less than 0.001). This was associated with reduced levels of linoleic acid and arachidonic acid in adipose tissue and tumour lipids with incorporation of n-3 fatty acids (all p less than 0.01 at least, analysis of variance). Moreover, the Maxepa diet produced significant reductions of plasma cholesterol, phospholipids and triglycerides (all p less than 0.01).