Abnormalities in fatty acids in plasma, erythrocytes and adipose tissue in Japanese patients with colorectal cancer.

AIM: In previous animal studies, we confirmed that linoleic acid (LNA) enhanced colon carcinogenesis, whereas eicosapentaenoic acid (EPA) had protective effects in azoxymethane-induced colon tumorigenesis. In regard to the protective effects of marine n-3 polyunsaturated fatty acids (PUFAs) on colorectal cancer however, evidence from epidemiological studies is inconsistent. MATERIALS AND METHODS: In the present study we investigated the fatty acid composition in plasma, red blood cells (RBCs) and adipose tissue from Japanese patients with colorectal cancer, or benign disease. RESULTS: Sixty-one patients with histologically-confirmed colorectal cancer and 42 patients with non-malignant disease were recruited for this study. The fatty acid composition of the total phospholipid (PL) fraction of plasma and washed RBCs was determined by gas chromatography. The fatty acid composition of the triacylglycerol (TAG) fraction of subcutaneous adipose tissue was determined in a similar manner. The EPA proportion in the plasma and RBC PL fractions was significantly lower in patients with cancer than in the controls (p<0.05). Similarly, the LNA proportion in the RBC PL fraction was lower in patients with cancer, but no changes were found in the plasma PL fraction. Arachidonic acid was the only PUFA in the adipose TAG fraction that exhibited significant differences, with higher levels in the patients with cancer than in the controls. CONCLUSION: Our findings suggest that patients with cancer have abnormalities in PUFAs in the plasma PL, erythrocyte PL, and adipose TAG fractions. Further investigation is needed to clarify the differences in the results between the various fractions.

Arachidonic acid supplementation during gestational, lactational and post-weaning periods prevents retinal degeneration induced in a rodent model.

Fatty acids and their derivatives play a role in the response to retinal injury. The effects of dietary arachidonic acid (AA) supplementation on N-methyl-N-nitrosourea (MNU)-induced retinal degeneration was investigated in young Lewis rats during the gestational, lactational and post-weaning periods. Dams were fed 0·1, 0·5 or 2·0% AA diets or a basal (< 0·01% AA) diet. On postnatal day 21 (at weaning), male pups received a single intraperitoneal injection of 50 mg MNU/kg or vehicle, and were fed the same diet as their mother for 7 d. Retinal apoptosis was analysed by the terminal deoxynucleotidyl transferase-mediated dUTP digoxigenin nick-end labelling (TUNEL) assay 24 h after the MNU treatment, and retinal morphology was examined 7 d post-MNU. Histologically, all rats that received MNU and were fed the basal and 0·1% AA diets developed retinal degeneration characterised by the loss of photoreceptor cells (disappearance of the outer nuclear layer and the photoreceptor layer) in the central retina. The 0·5 and 2·0% AA diets rescued rats from retinal damage. Morphometrically, in parallel with the AA dose (0·5 and 2·0% AA), the photoreceptor ratio significantly increased and the retinal damage ratio decreased in the central retina, compared with the corresponding ratios in basal diet-fed rats. In parallel with the increase in serum and retinal AA levels and the AA:DHA ratio, the apoptotic index in the central retina was dose-dependently decreased in rats fed the 0·5 and 2·0% AA diets. In conclusion, an AA-rich diet during the gestation, lactation and post-weaning periods rescued young Lewis rats from MNU-induced retinal degeneration via the inhibition of photoreceptor apoptosis. Therefore, an AA-enriched diet in the prenatal and postnatal periods may be an important strategy to suppress the degree of photoreceptor injury in humans.

Promoting effect of arachidonic acid supplementation on N-methyl-N-nitrosourea-induced pancreatic acinar cell hyperplasia in young Lewis rats.

Arachidonic acid (AA) is naturally found in human breast milk. AA, together with docosahexaenoic acid, is commonly added as a functional food ingredient to commercial infant formula worldwide, in accordance with the international standard of Codex Alimentarius. However, few studies have been performed that are concerned with the possible carcinogenic effects of AA supplementation during neonatal life. The effect of dietary AA supplementation in dams, during gestation and lactation, was investigated in N-methyl-N-nitrosourea (MNU)-induced preneoplastic lesions in the exocrine pancreas of young Lewis rats. Dams were fed either an AA (2.0% AA) or a basal (<0.01% AA) diet. On postnatal day 0 (at birth), male and female pups received a single intraperitoneal injection of either 35 mg/kg MNU or vehicle. The morphology and proliferating activity of the exocrine pancreas were examined by proliferative cell nuclear antigen immunohistochemistry 7, 14, 21, 28 and/or 60 days post-MNU. Histopathologically, acinar cell hyperplasia (ACH) occurred in the MNU-treated groups 60 days after MNU injection, irrespecitive of whether the rats had been fed an AA diet. Morphometrically, the number and area of ACH per 1 mm(2) in MNU-treated rats increased significantly in the AA diet-fed rats, compared with basal diet-fed rats. The number of proliferative cell nuclear antigen-positive acinar cells in both the normal and hyperplastic areas of MNU-treated rats increased significantly in the AA diet-fed rats. In conclusion, providing dams with an AA-rich diet during gestation and lactation promotes MNU-induced pancreatic ACH in young Lewis rats.

[A case of unresectable multiple hepatic metastases from ascending colon cancer successfully treated with panitumumab and FOLFIRI(5-FU/LV/irinotecan)therapy].

A 68-year-old man had undergone right hemicolectomy of ascending colon cancer with multiple liver metastases. This case of k-ras status on the cancer tissue also showed wild type. Chemotherapy with panitumumab and 5-FU/LV/irinotecan (FOLFIRI)regimen was performed after the resection of the ascending colon cancer. After seven curses of treatment, metastatic liver tumors were reduced considerably(PR). Liver resection(left hepatic lobectomy and partial resection of S4 and S5)and radiofrequency ablation therapy were performed. Recently, chemotherapy has improved overall survival of initially unresectable patients by allowing tumor downstaging and complete resection. Combination chemotherapy using panitumumab, and FOLFIRI plus operation is a candidate as a standard treatment strategy for multiple liver metastases of colon cancer.

[A case study of advanced gastric cancer patient treated with S-1+paclitaxel/lentinan].

A 47 -year-old male presented with gastric cancer, with right cervical and para-aortic lymph node metastases. The patient had not undergone a curative operation, but was treated with immunochemotherapy in combination with S-1 60 mg/m2(2 weeks administration and 2 weeks rest), paclitaxel 60 mg/m²(day 1, 8, 15), and Lentinan 2mg/body(day 1, 8, 15). After 3 courses of this treatment, no hot-spots were identified on cervical and para-aorta lymph nodes by PET-CT examination. We decided to perform total gastrectomy with D3 lymphadenectomy and Roux-en Y reconstruction. On histopathological examination, no malignancy was seen in the lymph nodes and the main tumor was judged to be grade 2. With this combined immunochemotherapy, the patient had a favorable outcome without side effects, which proved effective for far advanced gastric cancer.

Identification of oligosaccharides from histopathological sections by MALDI imaging mass spectrometry.

Direct tissue analysis using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) provides the means for in situ molecular analysis of a wide variety of biomolecules. This technology--known as imaging mass spectrometry (IMS)--allows the measurement of biomolecules in their native biological environments without the need for target-specific reagents such as antibodies. In this study, we applied the IMS technique to formalin-fixed paraffin-embedded samples to identify a substance(s) responsible for the intestinal obstruction caused by an unidentified foreign body. In advance of IMS analysis, some pretreatments were applied. After the deparaffinization of sections, samples were subjected to enzyme digestion. The sections co-crystallized with matrix were desorbed and ionized by a laser pulse with scanning. A combination of α-amylase digestion and the 2,5-dihydroxybenzoic acid matrix gave the best mass spectrum. With the IMS Convolution software which we developed, we could automatically extract meaningful signals from the IMS datasets. The representative peak values were m/z 1,013, 1,175, 1,337, 1,499, 1,661, 1,823, and 1,985. Thus, it was revealed that the material was polymer with a 162-Da unit size, calculated from the even intervals. In comparison with the mass spectra of the histopathological specimen and authentic materials, the main component coincided with amylopectin rather than amylose. Tandem MS analysis proved that the main components were oligosaccharides. Finally, we confirmed the identification of amylopectin by staining with periodic acid-Schiff and iodine. These results for the first time show the advantages of MALDI-IMS in combination with enzyme digestion for the direct analysis of oligosaccharides as a major component of histopathological samples.

Peroxidation of n-3 Polyunsaturated Fatty Acids Inhibits the Induction of iNOS Gene Expression in Proinflammatory Cytokine-Stimulated Hepatocytes.

Eicosapentaenoic acid and docosahexaenoic acid (EPA/DHA), n-3 polyunsaturated fatty acids (PUFAs), have a variety of biological activities including anti-inflammatory and anticancer effects. We hypothesized that their peroxidized products contributed in part to anti-inflammatory effects. In the liver, the production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been implicated as one of the factors in hepatic inflammation and injury. We examined whether the peroxidation of EPA/DHA influences the induction of iNOS and NO production in proinflammatory cytokine-stimulated cultured hepatocytes, which is in vitro liver inflammation model. Peroxidized EPA/DHA inhibited the induction of iNOS and NO production in parallel with the increased levels of their peroxidation, whereas unoxidized EPA/DHA had no effects at all. Peroxidized EPA/DHA reduced the activation of transcription factor, NF-κB, and the expression of the iNOS antisense transcript, which are involved in iNOS promoter transactivation (mRNA synthesis) and its mRNA stabilization, respectively. These findings demonstrated that peroxidized products of EPA/DHA suppressed the induction of iNOS gene expression through both of the transcriptional and posttranscriptional steps, leading to the prevention of hepatic inflammation.

Well-differentiated liposarcoma, an atypical lipomatous tumor, of the mesentery: a case report and review of the literature.

Mesenteric liposarcoma is a rare neoplasm. Here, we report the case of a 73-year-old Japanese man with a well-differentiated (WD) liposarcoma of the mesentery. Due to rapid growth of the abdominal mass and abdominal insufficiency, a tumorectomy was performed. The excised tumor was 12.4 × 9.6 cm in size and weighed 548 g. Cut sections showed a lobulated yellow and/or grayish-colored appearance. The histological features were predominantly those of the sclerotic and lipoma-like variants of WD liposarcoma. The cytoplasm of most spindle cells was diffusely immunoreactive for CD34, while fat cells were positive for S-100 protein. Some spindle cell nuclei were positive for CDK4, and a few were positive for MDM2. The average Ki-67 proliferation index in tumor cells was 10%, and androgen receptor expression was detected in tumor cell nuclei. The present case and 11 cases identified from a literature search were reviewed. The WD mesenteric liposarcomas developed in patients in the fourth to seventh decades of life (mean age 57.9 years). The patients consisted of 7 men and 5 women. All tumors were larger than 10 cm in diameter at the time of surgery. Complete resection might be the only curative therapy for WD liposarcomas of the mesentery, but long-term follow-up is needed because of the possibility of a local recurrence of the tumor.

Short-term pregnancy hormone treatment of N-methyl-N-nitrosourea-induced mammary carcinogenesis in relation to fatty acid composition of serum phospholipids in female Lewis rats.

AIM: Short-term oestrogen and progesterone treatment (STEPT) mimics the pregnancy hormone milieu. This study compared the development of N-methyl-N-nitrosourea (MNU)-induced mammary cancer in female Lewis rats that received STEPT in early or later life. MATERIALS AND METHODS: Rats in Groups 1 and 2 received a single intraperitoneal injection of 50 mg/kg MNU at 4 weeks old. Pellets containing 0.5 mg 17beta-estradiol and 32.5 mg progesterone (EP) were subcutaneously implanted in rats in Group 1 during 6-9 weeks old. Rats in Groups 3 and 4 received 50 mg/kg MNU at 22 weeks old and again at 23 weeks old. EP pellets were implanted in rats in Group 3 during 24-27 weeks old. At the time of EP removal and 8 weeks afterward, 4 randomly selected rats in each group were sacrificed for blood sampling. The fatty acid composition of serum phospholipids was measured by capillary gas chromatography. The remaining rats were sacrificed when they developed mammary tumours >or=1 cm in diameter or at the termination of the experiment, which was at 18 weeks old for Groups 1 and 2 and at 64 weeks old for Groups 3 and 4. Mammary cancer was histologically confirmed. RESULTS: Group 1 had a significantly suppressed incidence of mammary cancer compared to Group 2 (7% vs. 90%), whereas the cancer incidence in Group 3 was similar to that of Group 4 (50% vs. 56%). Rats in Group 1 had significantly smaller n-6/n-3 polyunsaturated fatty acid (PUFA) ratios and higher levels of docosahexaenoic acid (DHA) than those in Group 2 at the time of EP removal but not 8 weeks after EP removal. Neither the PUFA ratios nor the DHA levels differed between Groups 3 and 4 at any time. These data suggest that the age at which STEPT is administered is important, since its mammary cancer-suppressing potential was lost in aged animals. CONCLUSION: DHA and the n-6/n-3 PUFA ratio may play a crucial role in mammary cancer suppression by STEPT.

Effects of eicosapentaenoic acid on biochemical failure after radical prostatectomy for prostate cancer.

AIM: To study the effects of eicosapentaenoic acid (EPA) on prostate-specific antigen (PSA) failure in prostate cancer patients who underwent prostatectomy. PATIENTS AND METHODS: Sixty-two prostate cancer patients whose PSA levels were less than 0.2 ng/ml 3 months after surgery were randomized to either an EPA group (n=32) or a control group (n=30). EPA (2.4 g/day) was administered in the EPA group for 2 years. PSA was measured every two months. RESULTS: The EPA concentration increased but the docosahexaenoic acid concentration decreased significantly (P<0.001) in erythrocytes. The PSA recurrence rates during a mean follow-up of 53.8 months were not different between the two groups (p=0.16). CONCLUSION: A longer and/or larger intervention or docosahexaenoic acid supplementation might be necessary to identify significant preventive effects of mega-3 polyunsaturated fatty acids on PSA recurrence.

Fatty acid composition of plasma, erythrocytes and adipose: their correlations and effects of age and sex.

The composition of fatty acids in abdominal subcutaneous adipose tissue and the correlation of fatty acid values of plasma and erythrocytes had not been reported in Japan. The aim of the present study was to investigate the fatty acid composition and correlation of plasma and erythrocyte phospholipids (PL) and adipose triacylglycerols (TG) in 75 adult patients admitted for non-malignant diseases. We also examined the relationship of n-3 and n-6 polyunsaturated fatty acid (PUFA) with patients' characteristics. The total n-3 PUFA were 11.2, 11.8 and 1.9%, and the ratios of n-6/n-3 were 2.41, 1.87 and 8.20 in plasma and erythrocyte PL and adipose TG, respectively. There were the highest correlations for total n-3 PUFA and the n-6/n-3 ratio between plasma and erythrocyte PL and adipose TG. There was a positive correlation between n-3 PUFAs and age, but a negative correlation was found between n-6 PUFAs and age. There was no significant difference in the values of PUFAs in plasma and erythrocyte PL and adipose TG between men and women. The patients with cholesterol cholecystolithiasis showed a significantly lower proportion of eicosapentaenoic acid in plasma and erythrocyte PL than those of the other patients. Our findings suggest that PUFA in plasma and erythrocyte PL may be good biomarkers and more acceptable for studying participants than adipose TG.

Surgical Control of a Primary Hepatic Carcinoid Tumor: A Case Report.

We report a primary hepatic carcinoid tumor occurring in a 47-year-old man. The patient consulted our hospital complaining of epigastralgia. Abdominal ultrasonography, computed tomography scanning, and magnetic resonance imaging showed a large mass in the right lobe of the liver. FDG-PET revealed 18F-FDG uptake by the right hepatic lobe. The tumor was a solid mass with cystic components, approximately 15 cm in diameter. We conducted an extended right lobectomy of the liver. The resected specimen was a solid tumor with cystic components and hemorrhagic lesion. Microscopic findings showed that the tumor cells had round nuclei and formed trabecular patterns. Immunohistologically, tumor cells were stained positive for chromogranin A, neuron specific enolase, CD56, and S-100. Careful examinations before and after the operation revealed no other possible origin of the tumor. Based on these findings, the tumor was diagnosed as a primary hepatic carcinoid. This is a report of a rare case of a primary hepatic carcinoid tumor with a discussion of several other relevant reports.

Overproduction of PGE2 in peripheral blood monocytes of gastrointestinal cancer patients with mucins in their bloodstream.

When monocytes from healthy donors were cultured in the presence of sera from patients with gastrointestinal cancer, PGE2 production from the monocytes was elevated. Serum proteins were fractionated on Sepharose 4B and the inducing activity was found in the excluded fractions. By excluding some mucins from the serum, the inducing activity was reduced effectively. The activity was also reduced by adding binding inhibitors to the scavenger receptor. These results suggest that peripheral blood monocytes in epithelial cancer patients may be continuously stimulated by mucins in the bloodstream through the scavenger receptor, resulting in overproduction of PGE2.

The effect of eicosapentaenoic acid on prostate-specific antigen.

The "Study of EPA Effects on Prostate Cancer" (SEEPC) Group has been conducting a clinical trial with patients who underwent radical prostatectomy. The main purpose of the SEEPC is to evaluate whether eicosapentaenoic acid (EPA) prevents prostate cancer (PC) recurrence. As the surrogate marker of recurrence, the prostate-specific antigen (PSA) level was measured. However, if EPA affects the PSA values independently of PC, PSA may not be a good marker of recurrence in the event of EPA treatment. Thus, in the present study, whether EPA affected the PSA values was investigated using non-PC volunteers. Twenty men, of at least 50 years of age, were recruited, mostly from hospital staff The volunteers were randomly allocated either to the EPA group or the control. The subjects in the EPA group were administered EPA-ethyl ester a dose of 2400 mg/day for 12 weeks, whereas the controls were administered none. Fasting blood samples were obtained before the start of EPA administration and 4 and 12 weeks later. The EPA concentrations in erythrocytes increased in all the subjects in the EPA group (174+/-96%) with no significant changes in the control group (8.5+/-14.0%). There were no significant differences between the two groups in the serum PSA levels, allowing the conclusion that the PSA is an appropriate surrogate marker of recurrence in prostate cancer.

[Three cases of drug-induced akathisia due to antiemetics during cancer palliative care].

Three cases of drug-induced akathisia during palliative care in terminal cancer patients were reported. Antiemetics (metoclopramide and prochlorperazine) possessing a central antidopaminergic effect were suspected to have caused the akathisia. Akathisia, as well as extrapyramidal symptoms, is a common and unpleasant complex neurobehavioral adverse effect of conventional antipsychotic drugs. But it is not widely recognized by general clinicians. This syndrome consists of subjective (feeling of inner restlessness, mental unease, or dysphoria and the urge to move) and objective components (restless movement, including rocking on one's feet, walking in position shuffling and tramping the legs,and crossing and uncrossing one's legs while sitting). In severe cases, patients constantly pace up and down in an attempt to relieve the sense of unrest. While the pathophysiology of drug-induced akathisia remains unknown, antagonism of the mesocortical and mesolimbic dopaminergic pathways is a plausible if not completely satisfactory hypothesis. The notion that dopaminergic blockade underlies the emergence of akathisia is supported by the PET studies. Since akathisia is a drug-induced adverse effect, optimal management involves its prevention rather than treatment. Drugs which have been found to have some efficacy in the treatment of akathisia are anticholinergics, beta-blockers, benzodiazepines and clonidine. Though a number of other treatments have been proposed, no trial-based evidences for treatment of akathisia have been available. It is important that akathisia is recognized and treated appropriately as an adverse reaction to drugs and a further increase in antipsychotic medication dosage may further exacerbate the condition.

Enhanced production of interleukin 6 in peripheral blood monocytes stimulated with mucins secreted into the bloodstream.

PURPOSE: It has been reported that tumor progression is correlated with the serum level of interleukin 6 (IL-6). The purpose of this study was to investigate by what mechanism, other than production from tumor cell, the serum level of IL-6 is elevated in the tumor-bearing state. EXPERIMENTAL DESIGN: Monocytes from healthy donors were cultured in the presence of sera from colon cancer patients, and the activity to elevate IL-6 production was estimated. This activity of serum was also examined after various biochemical treatments. RESULTS: When monocytes from healthy donors were cultured in the presence of sera from patients with colon cancer, secretion of IL-6 from the cells was markedly elevated. Serum proteins were fractionated on Sepharose 4B and the activity to elevate IL-6 production was found in the excluded fractions. Sialyl Tn antigen was detected in these same fractions. By excluding some mucins from the serum, the inducing activity was reduced to 40% of the original level. Furthermore, we purified mucins from the conditioned medium of colon cancer cells. Production of IL-6 was effectively elevated by a small amount of purified mucins in a dose-dependent manner. When the inducing activity was examined in the presence of binding or competitive inhibitors to the scavenger receptor, the effect was remarkably reduced. CONCLUSIONS: Mucins secreted from colon cancer cells into the bloodstream induce production of IL-6 in peripheral blood monocytes through the scavenger receptor, which may be responsible for the high level of serum IL-6 in colon cancer patients.

Conjugated docosahexaenoic acid is a potent inducer of cell cycle arrest and apoptosis and inhibits growth of colo 201 human colon cancer cells.

The effect of conjugated docosahexaenoic acid (CDHA) on the inhibition of colon cancer cell growth was examined in the colo 201 human colon cancer cell line, and the effect was compared with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). CDHA was a more potent tumor cell growth inhibitor than DHA and EPA by colorimetric 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay (IC50 for 72 h: 31.6 microM, 46.8 microM, and 56.6 microM, respectively). CDHA inhibited cell cycle progression, due to accumulation of cells in G1 phase, which involved increased p21Cip1/Waf1 and decreased cyclin D1, cyclin E, and proliferating cell nuclear antigen expression; the p53 and cyclin A levels were unchanged. Induction of apoptosis was confirmed by the appearance of sub-G1 populations, and apoptosis cascade involved upregulation of the apoptosis-enhancing proteins (Bak and Bcl-xS) and downregulation of the apoptosis-suppressing proteins (Bcl-xL and Bcl-2). CDHA modulated cell cycle regulatory proteins and apoptosis-related proteins, similar to the effects of DHA. CDHA at a dietary dose of 1.0% significantly inhibited growth of colo 201 cells transplanted in nude mice.

Dietary effects of conjugated docosahexaenoic acid on N-methyl-N-nitrosourea-induced mammary carcinogenesis in female Sprague-Dawley rats.

The dietary effects of conjugated docosahexaenoic acid (CDHA) were examined in an N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinogenesis model. Female Sprague-Dawley rats were administered 50 mg/kg MNU intraperitoneally at 49 days of age. A powdered AIN-76A diet containing 0, 0.2 or 1.0% CDHA was fed to the rats from 21 to 49 days of age (before MNU; pre-initiation phase) or from 49 days to 40 weeks of age (after MNU; post-initiation phase). Rats were sacrificed when their largest mammary tumor was > or =1 cm in size or when they reached 40 weeks of age. All histologically detected mammary carcinomas were evaluated. In rats that received CDHA after MNU, development of mammary carcinoma > or =1 cm was inhibited, and there was a significant decrease in the final mammary cancer incidence and multiplicity, compared with rats that did not receive CDHA. Consumption of the 0.2% CDHA diet after MNU significantly prolonged latency. Suppression of mammary cancer yield by consumption of a CDHA diet after MNU administration was not dose-dependent. In rats that received CDHA before MNU, suppression of mammary cancer was not observed. These results indicate that CDHA administration in the post-initiation period suppressed mammary carcinogenesis, whereas CDHA administration in the pre-initiation period was ineffective.

Conjugated docosahexaenoic acid suppresses KPL-1 human breast cancer cell growth in vitro and in vivo: potential mechanisms of action.

INTRODUCTION: The present study was conducted to examine the effect of conjugated docosahexaenoic acid (CDHA) on cell growth, cell cycle progression, mode of cell death, and expression of cell cycle regulatory and/or apoptosis-related proteins in KPL-1 human breast cancer cell line. This effect of CDHA was compared with that of docosahexaenoic acid (DHA). METHODS: KPL-1 cell growth was assessed by colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay; cell cycle progression and mode of cell death were examined by flow cytometry; and levels of expression of p53, p21Cip1/Waf1, cyclin D1, Bax, and Bcl-2 proteins were examined by Western blotting analysis. In vivo tumor growth was examined by injecting KPL-1 cells subcutaneously into the area of the right thoracic mammary fat pad of female athymic mice fed a CDHA diet. RESULTS: CDHA inhibited KPL-1 cells more effectively than did DHA (50% inhibitory concentration for 72 hours: 97 micromol/l and 270 micromol/l, respectively). With both CDHA and DHA growth inhibition was due to apoptosis, as indicated by the appearance of a sub-G1 fraction. The apoptosis cascade involved downregulation of Bcl-2 protein; Bax expression was unchanged. Cell cycle progression was due to G0/G1 arrest, which involved increased expression of p53 and p21Cip1/Waf1, and decreased expression of cyclin D1. CDHA modulated cell cycle regulatory proteins and apoptosis-related proteins in a manner similar to that of parent DHA. In the athymic mouse system 1.0% dietary CDHA, but not 0.2%, significantly suppressed growth of KPL-1 tumor cells; CDHA tended to decrease regional lymph node metastasis in a dose dependent manner. CONCLUSION: CDHA inhibited growth of KPL-1 human breast cancer cells in vitro more effectively than did DHA. The mechanisms of action involved modulation of apoptosis cascade and cell cycle progression. Dietary CDHA at 1.0% suppressed KPL-1 cell growth in the athymic mouse system.

Phase II study of oral S-1 for treatment of metastatic colorectal carcinoma.

BACKGROUND: The goal of the current study was to evaluate the objective response rate and toxicity associated with the oral fluoropyrimidine S-1 (a combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate) in patients with previously untreated metastatic colorectal carcinoma. METHODS: Thirty-eight patients were enrolled in the study. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 28 days, followed by a 14-day rest period. Treatment was repeated every 6 weeks unless disease progression was observed. RESULTS: A combined total of 173 courses of S-1 were administered to the 38 enrolled patients. The median number of courses administered to a given patient was 3.5 (range, 1-18). Although no patient exhibited a complete response to treatment, 15 had partial responses (response rate, 39.5%; 95% confidence interval, 24.0-56.6%). In addition, 5 patients had minor responses, and 14 had stable disease. Four patients were found to have progressive disease after two courses of treatment. The median survival time was 358 days (95% confidence interval, 305-490 days), and the 1-year survival rate was 47.4%. The most common adverse reactions included myelosuppression and gastrointestinal toxicity; most cases involved Grade 1 or 2 toxicity, but Grade 3 toxicities (anemia [7.9% of patients], neutropenia [5.3% of patients], diarrhea [2.6% of patients], and abnormal bilirubin levels [7.9% of patients]) also were noted. Neither Grade 4 toxicity nor treatment-related death was observed during the study. CONCLUSIONS: Orally administered S-1 is active against metastatic colorectal carcinoma and has an acceptable toxicity profile. This promising agent has the potential to become a valuable chemotherapeutic option.