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New Abstracts 4/14/02 - 4/21/02

New Abstracts of interest from a PUBMED search (colon OR colorectal OR chemoprevention) AND cancer.

Cimetidine (Tagamet)

4/16/02 Cimetidine modulates the antigen presenting capacity of dendritic cells from colorectal cancer patients Br J Cancer 2002 Apr 22;86(8):1257-61 PMID: 11953882 Our results suggest that cimetidine may enhance the host's antitumour cell-mediated immunity by improving the suppressed dendritic cells function of advanced cancer patients.

Fish Oil
4/16/02 Differential modulation of transforming growth factor-betas and cyclooxygenases in the platelet lysates of male F344 rats by dietary lipids and piroxicam Mol Cell Biochem 2002 Feb;231(1-2):139-46 PMID: 11952155 Platelets are implicated in the pathogenesis of various chronic diseases including cancer. The main objective of the present study was to determine if dietary fish oil and piroxicam, known modulators of colon tumorigenesis, effect transforming growth factor (TGF)-betas and cyclooxygenase (COX) isozymes in the platelets of colon tumor-bearing male F344 rats... This supports the conjecture that the levels of bioactive constituents of the platelets are profoundly modulated by dietary lipids, which in turn could influence the pathogenesis of chronic illnesses.

Black Raspberries
4/20/02 Effects of lyophilized black raspberries on azoxymethane-induced colon cancer and 8-hydroxy-2'-deoxyguanosine levels in the Fischer 344 rat. Nutr Cancer 2001;40(2):125-33 PMID: 11962247 AOM-treated rats began consuming diets containing 0%, 2.5%, 5%, or 10% (wt/wt) BRB Although not significant, a decrease in tumor burden (28%, 42%, and 75%) was observed in all BRB groups. Adenocarcinoma multiplicity decreased 28%, 35%, and 80% (P < 0.01) in the same treatment groups

Chemoprevention
4/16/02 Prospects for chemoprevention of cancer J Intern Med 2002 Apr;251(4):286-300 PMID: 11952879 The recent progress in molecular biology and pharmacology has increased the likelihood that cancer prevention will rely increasingly on interventions collectively termed 'chemoprevention'. Cancer chemoprevention is the use of agents to inhibit, delay or reverse carcinogenesis. A number of potential targets for chemoprevention have recently been identified. Many classes of agents including antioestrogens, anti-inflammatories, antioxidants and other diet-derived agents have shown a great deal of promise. In this review, we will begin by describing the general classes of chemopreventive agents and the mechanisms by which these agents act. We will then describe the opportunities that presently exist for chemoprevention of specific cancers.

Surgery
4/16/02 Surgical treatment of liver metastases. Semin Oncol 2002 Apr;29(2):107-18 PMID: 11951208 Approximately 50% to 60% of patients with colorectal cancer will develop hepatic metastases during the course of their illness, with 20% to 30% of patients having liver metastases at time of diagnosis. In nearly a quarter of these patients the liver is the only site of disease. Surgical resection of isolated hepatic metastases has been associated with a 27% to 37% 5-year survival and confers a survival advantage compared to patients not undergoing resection. Thorough preoperative and intraoperative evaluation is necessary to select appropriate surgical candidates who may benefit from resection. This article examines criteria useful in patient selection, and also reviews the management of recurrent hepatic metastases and the role of repeat hepatic resection

Nitric Oxide

This is interesting because there are herbal inhibitors of Nitric Oxide, e.g. Ginko Biloba
4/16/02 NO-releasing NSAIDs and colon cancer chemoprevention: A promising novel approach (Review). Int J Oncol 2002 May;20(5):885-90 PMID: 11956579 That NSAIDs decrease the incidence of and mortality from colon cancer has been a major advance in chemoprevention. These compounds are, however, limited by their significant side effects. NO-releasing NSAIDs (NO-NSAIDs) are a novel class of compounds, synthesized to overcome the limitations of NSAIDs. In general, they appear safer and much more effective than their traditional counterparts. We review their structural features, metabolism and pharmacological actions. In vitro and in vivo studies indicate that they are much more effective than traditional NSAIDs in modulating colonocyte kinetics and the formation of premalignant colon lesions. Their mechanism of action is complex and not fully understood, including modulation of NO synthesis, signaling mediated via NF-kappaB and likely other pathways. Current early findings indicate that NO-NSAIDs may play a highly promising role in the chemoprevention of colon cancer
4/16/02 Nitric oxide of human colorectal adenocarcinoma cell lines promotes tumour cell invasion. Br J Cancer 2002 Apr 22;86(8):1310-5 PMID: 11953890 The present study investigates the role of nitric oxide and the involvement of nitric oxide synthase II isoform on the invasion of human colorectal adenocarcinoma cell lines HRT-18 and HT-29... Therefore, the production of nitric oxide and secretion of pro-inflammatory cytokines by tumour-associated macrophages, which in turn induce nitric oxide synthase II isoform in tumour cells, promotes tumour cell invasiveness.
4/16/02 Suppression of promoter-dependent transcriptional activity of inducible nitric oxide synthase by sodium butyrate in colon cancer cells Cancer Lett 2002 Mar 28;177(2):155-61 PMID: 11825662 Butyrate suppresses the growth of colon cancer cells, inducing differentiation and apoptosis in vitro. Increased expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) has been suggested to be closely involved in colon carcinogenesis. In this study, effects of sodium butyrate on the promoter-dependent transcriptional activity of iNOS and COX-2 genes were investigated in a colon cancer cell line, DLD-1, using a reporter gene assay system. Sodium butyrate significantly reduced promoter-dependent iNOS transcriptional activity dose-dependently at concentrations higher than 0.1 mM. COX-2 transcriptional activity was not suppressed, but slightly increased. While hyperacetylated histones appeared at concentrations of sodium butyrate suppressing iNOS gene promoter activity, promoter-dependent transcriptional activities of iNOS and COX-2 genes were both increased by the histone deacetylase inhibitor trichostatin A. These results suggested that sodium butyrate exhibits differential effects on iNOS and COX-2 genes, acting to suppress iNOS expression via mechanisms independent of histone acetylation
4/16/02 Nitric oxide synthase inhibitor and IL-18 enhance the anti-tumor immune response of rats carrying an intrahepatic colon carcinoma Cancer Immunol Immunother 2001 Nov;50(9):491-501 PMID: 11761444 We conclude that NOS inhibitors in combination with immunostimulatory cytokines, such as IL-18, could be useful tools to enhance anti-tumor immune responses in TB rats and therefore to increase the efficiency of immunotherapies.

Nuclear Factor Kappa B

This is interesting because there are herbal inhibitors of NF-kappaB, e.g. Stinging Nettle
4/16/02 [Activation of nuclear factor-kappaB and effects of anti-inflammatory treatment thereon in intestinal mucosa of patients with ulcerative colitis] Zhonghua Yi Xue Za Zhi 2002 Mar;82(6):384-8 PMID: 11953203 CONCLUSION: The increased activation of NF-kappaB and increased expression of NF-kappaB may be involved in the pathogenesis of UC. Glucocorticoids and SASP strongly inhibited NF-kappaB activation and expression. The inhibition of NF-kappaB activation may be a central part of the anti-inflammatory action of glucocorticoids and SASP, which might represent an important pharmacological mechanism in treatment of patients with UC. NF-kappaB will be an important target for cytokine-based therapy of UC
4/16/02 Nuclear factor kappa B signaling in catabolic disorders Curr Opin Clin Nutr Metab Care 2002 May;5(3):255-63 PMID: 11953650 The nuclear factor kappaB family of inducible transcription factors regulates the expression of many genes. Nuclear factor kappaB has been implicated in autoimmune and inflammatory diseases, infection, cell survival, and cell transformation with subsequent promotion of cancer. In this review, we summarize features of nuclear factor kappaB regulation in several catabolic disorders, and describe its role in normal cellular function as well as provide an important link to the role of scaffold proteins, cellular receptors, and other cell signaling pathway kinases that converge on the nuclear factor kappaB signaling cascade. Subsequently, we focus on the role of nuclear factor kappaB in cell survival and oxidative stress. Finally, potential therapeutic strategies are discussed that may modify nuclear factor kappaB activity including endogenous antioxidant systems and the Fas/FasL system. However, challenges still remain in developing new therapeutic strategies that not only include identifying novel agents, but also by improving clinical endpoint definitions and by defining biological efficacy

Therasphere
4/16/02 Radioembolization for hepatic metastases. Semin Oncol 2002 Apr;29(2):152-9 PMID: 11951213 In a phase I/II study, 37 patients with metastatic liver disease, predominantly from colorectal cancer (n = 33) were treated between 1986 and 1994 by intrahepatic arterial embolization of radioactive yttrium 90 (Y 90) glass microspheres. The calculated total liver dose increased in stages from 5,000 cGy to 15,000 cGy. Mean follow-up was 8 months (range, 1 to 49). No major procedural, hematologic, or pulmonary complications occurred. Late gastroduodenal ulceration occurred early in the study at 6 to 8 weeks in three patients with a history of chronic alcohol abuse and was treated successfully medically. Of 30 patients with either computed tomography (CT) or sonography follow-up for 4 months or longer, 15 had tumor involvement in the liver that was diffuse, irregular, or infiltrating with mixed or poor vascularity and thus definitive imaging changes could not be appreciated on follow-up. In 15 patients with identifiable marker lesions with developed hypervascularity, post-treatment beneficial effects were noted. In seven of these patients followed by CT, decreased tumor attenuation and sharper definition of tumor-liver interface were noted. Findings on sonography in eight patients were increased tumor sonolucency centrally, consistent with liquefaction necrosis, and rim hyperechogenicity, consistent with calcification. A 25% to 40% decrease in area of marker lesions occurred in five patients and one other patient had small 1.0- to 1.5-cm lesions disappear temporarily on sonography. In conclusion, this method provides a feasible single-session technique for treatment of hepatic metastases. Complications are low and if the tumor pattern is nodular with some hypervascularity, beneficial effects are observed clinically and on imaging studies

Chemoembolization
4/16/02 Hepatic artery chemoembolization. Semin Oncol 2002 Apr;29(2):145-51 PMID: 11951212 Chemoembolization is a technique that can deliver high concentrations of therapeutic agents directly to the liver for prolonged periods. Considerable experience has been gained in the treatment of hepatocellular carcinoma, where it appears to be a safe procedure that provides survival advantage over conservative therapy. There is much less experience in the treatment of hepatic metastases. Patients with carcinoid, pancreatic islet cell tumor, and sarcoma metastatic to the liver do appear to benefit from chemoembolization. Efficacy in other groups, such as patients with colorectal cancer metastatic to the liver, is less well established, but a recently initiated multicenter trial may resolve this issue. Semin Oncol 29:145-151

Liver Radiation
4/16/02 External-beam radiotherapy in the management of liver metastases Semin Oncol 2002 Apr;29(2):196-201 PMID: 11951218 This review discusses the importance of palliation of liver metastases. Although colorectal cancer comprises the majority of patients with metastatic liver disease, a number of other malignancies can be involved. Palliation of metastatic disease to liver has generally not included the use of external-beam radiotherapy because of restricted liver tolerance to radiotherapy. However, more recently, treatment policies have evolved to more generous use of palliative radiotherapy with utilization of tumor boost doses to partial liver volumes. This has resulted in improvement in palliation and a suggestion of improved survival with higher radiotherapy doses, which have been well tolerated by small volumes of liver

Isolated Hepatic Perfusion (IHP)
4/16/02 Transarterial perfusion of liver metastases Semin Oncol 2002 Apr;29(2):136-44 PMID: 11951211 Progressive growth of unresectable metastatic or primary malignancies confined to the liver is a significant clinical problem. Approximately 25% of patients with colorectal cancer will develop metastatic disease exclusively or largely confined to liver, the vast majority of which are not amenable to surgical resection. Despite aggressive systemic or regional chemotherapy, survival is only 12 to 18 months. More than 80% of patients with ocular melanoma develop liver metastases as the first site of recurrent disease, and death from hepatic disease progression typically occurs 2 to 7 months after diagnosis. In addition, the liver is also the preferred site of metastatic disease for gastrointestinal or pancreatic neuroendocrine tumors. A number of physiological and anatomic features of the liver make it an ideal organ for regionally directed therapy to allow dose intensification to the cancer-burdened area while reducing or eliminating unnecessary systemic toxicity. To that end, complete vascular isolation and perfusion of the liver using a recirculating extracorporeal circuit, also called isolated hepatic perfusion (IHP), has been under clinical evaluation at our institution and others. In this article, we review the current results with IHP and its potential utility in the treatment of patients with unresectable hepatic malignancies

Hepatic Arterial Infusion
4/16/02 Intrahepatic arterial infusion of chemotherapy: Clinical results. Dizon DS, Kemeny NE. Semin Oncol 2002 Apr;29(2):126-35 PMID: 11951210 Approximately 60% of patients diagnosed with colorectal cancer (CRC) will go on to develop hepatic metastases. Although surgical resection is the only curative modality, a majority will not be able to undergo surgery. Alternative methods for treating this population have focused on the feasibility of hepatic arterial infusion (HAI) of chemotherapy. Randomized data in this field have been hampered due to small numbers of patients in some trials, or crossover between groups. However, most trials have suggested an improvement in both overall and progression-free survival with HAI therapy. Dose-limiting toxicity associated with HAI is related to hepatobiliary sclerosis, which has been reduced with the use of dexamethasone as part of the treatment. Current research is underway to improve the rate of extrahepatic metastases in patients undergoing HAI

PSK
4/16/02 Effectiveness of immunochemotherapy with PSK, a protein-bound polysaccharide, in colorectal cancer and changes of tumor marker Oncol Rep 2002 May-Jun;9(3):635-8 PMID: 11956642 In the present study, curatively resected patients of colorectal cancer at pTNM stages II and III were selected. Patients receiving postoperative combined PSK, a protein-bound polysaccharide, and fluoropyrimidine therapy (PSK + chemotherapy group) were compared with patients receiving postoperative chemotherapy alone (chemotherapy group) during the same period of study. Three-year disease-free survival rates were evaluated and the postoperative changes of serum type IV collagen level were investigated. The results confirmed a significant improvement of the three-year disease-free survival rate in the PSK + chemotherapy group compared to the chemotherapy group, suggesting that PSK is useful as postoperative prognosis control including relapse prevention for colorectal cancers at pTNM stage II and III. Analysis of the postoperative changes of serum type IV collagen level showed significantly higher levels in the chemotherapy group than in the PSK + chemotherapy group, and this tendency was sustained for 12 months after surgery. This observation is speculated to be caused by inhibition of vascular basement membrane destruction by PSK, leading to inhibition of release of type IV collagen into the blood. These results indicated a possibility that combined PSK and chemotherapy inhibited metastasis, thereby reducing the risk of relapse and leading to improvement of the three-year disease-free survival rate.

Predicting Response to 5-FU
4/16/02 Thymidine phosphorylase and dihydropyrimidine dehydrogenase levels in primary colorectal cancer show a relationship to clinical effects of 5'-deoxy-5-fluorouridine as adjuvant chemotherapy. Oncol Rep 2002 May-Jun;9(3):479-82 PMID: 11956613 although there were no significant differences in clinicopathologic features between high and low median TP level groups, disease-free survival was better in the high TP than in the low TP group (89% vs. 64%, at year 4); and c) of patients classified into 4 groups such as high TP/DPD, high TP but low DPD, low TP but high DPD, and low TP/DPD, patients with high TP but low DPD had the best disease-free survival, whereas the low TP but high DPD group had the worst survival. These results suggest that TP and DPD levels in primary colorectal tumors may be a useful indicator for selecting patients likely to respond to 5'-DFUR adjuvant chemotherapy and probably capecitabine, a prodrug of 5'-DFUR

Conformal Radiation
4/16/02 Clinical outcomes of 3D conformal hypofractionated single high-dose radiotherapy for one or two lung tumors using a stereotactic body frame. Int J Radiat Oncol Biol Phys 2002 Mar 15;52(4):1041-6 PMID: 11958900 Results: The initial 3 patients received 40, and the remaining 37 patients received 48 Gy after dose escalation. Of the 33 tumors followed >6 months, 6 tumors (18%) disappeared completely after treatment. Twenty-five tumors (76%) decreased in size by 30% or more after treatment. Therefore, 31 tumors (94%) showed a local response. During the follow-up of 4-37 months (median 19), no pulmonary complications greater than National Cancer Institute-Common Toxicity Criteria Grade 2 were noted. Of the 16 patients with histologically confirmed T1N0M0 primary lung cancer who received 48 Gy, all tumors were locally controlled during the follow-up of 6-36 months (median = 19). In 9 tumors with lung metastases that were irradiated with 48 Gy in total, 2 tumors did not show a local response. Finally, 3 tumors (33%) with lung metastases relapsed locally at 6-12 months (median 7) after treatment during the follow-up of 3-29 months (median 18).

Chronotherapy
4/20/02 Chronotherapy of colorectal cancer. Chronobiol Int 2002 Jan;19(1):207-19 PMID: 11962676 Chronotherapy consists of chemotherapy delivery according to circadian rhythms. These genetically based rhythms modulate cellular metabolism and cell proliferation in normal tissues. As a result, both the host tolerance and antitumor efficacy of 5-fluorouracil (5-FU) and oxaliplatin (L-OHP), like 30 other anticancer drugs, vary largely according to the dosing time in laboratory rodents. The transfer of this concept to the clinic is aimed primarily at increasing the dose-intensity of the therapy through adjustment of drug-delivery to 24h rhythms in host tolerance. A specific technology (programmable-in-time infusion pumps) enables administration of chronotherapy to fully ambulatory patients. Phase I-III clinical trials show chronotherapy significantly increases tolerance to high doses of cancer drugs and improves antitumor activity in patients with metastatic colorectal cancer. These safe conditions of drug-delivery led to the first demonstration of the high activity of the 5-FU-leucovorin-L-OHP protocol. Chronotherapy with these three drugs also allows surgical removal of previously unresectable liver and lung metastases. This novel medico-surgical management provides hope for the cure of metastatic disease in patients with unresectable colorectal cancer metastases
4/20/02 Clinical pharmacokinetics of 5-fluorouracil with consideration of chronopharmacokinetics. Chronobiol Int 2002 Jan;19(1):177-89 PMID: 11962674 Circadian rhythmicity in DPD activity is suggested from both human and animal investigations. In patients receiving protracted low dose 5-FU infusion, the circadian rhythm in FU plasma concentration peaks at 11:00h and is lowest at 23:00h, on average. The inverse relationship observed between the circadian profile of FU plasma concentration and PBMC-DP activity in these same patients suggests a link between DPD activity and FU pharmacokinetics. The impact of the biological time of drug administration was also studied with short venous infusions; clearance was 70% greater at 13:00h than at 01:00h. Similarly, peak drug concentration occurred in the first half of the night in patients receiving constant rate 5-FU infusion for 2-5d. Several studies describe wide interindividual variation in the timing of the peak and trough of the 24h rhythm in DPD activity. The rational for FU chronomodulated therapy has been the circadian rhythm in host drug tolerance, which is greatest during the night time when the proliferation of normal target tissue is least. A randomized study of chronomodulated FU therapy with maximal delivery rate at 04:00h was shown clearly to be significantly more effective and less toxic than control flat FU therapy. Future research must focus on easy-to-obtain markers of specific rhythms to individualize the chronomodulated FU delivery
4/20/02 Contribution of the rest-activity circadian rhythm to quality of life in cancer patients. Chronobiol Int 2002 Jan;19(1):313-23 PMID: 11962684 The relation between the individual rhythm in activity and QoL was investigated in 200 patients with metastatic colorectal cancer...The rest-activity circadian rhythm appeared to be an objective indicator of physical welfare and QoL. This analysis suggests that circadian function may be one of the biological determinants of QoL in cancer patients.
4/20/02 Quality of life and chronotherapy. Chronobiol Int 2002 Jan;19(1):299-312 PMID: 11962683
4/20/02 Pharmaco-economic comparative evaluation of combination chronotherapy vs. standard chemotherapy for colorectal cancer Chronobiol Int 2002 Jan;19(1):289-97 PMID: 11962682 Results of recent trials comparing combination chemotherapy consisting of 5-fluorouracil (5-FU), folinic acid (FOL), and oxaliplatin, given either as flat (A) or chronomodulated (B) infusion for metastatic colorectal cancer, were subjected to pharmaco-economic evaluation. The overall cost of treatment with the flat and chronomodulated protocols was equivalent. The expense of the delivery of medications with the chronotherapeutic arm (B) was greater than with the standard arm (A) because it was feasible to administer more courses (requiring more frequent doctor visits) and higher doses (high cost of medications) with containment of toxic reactions. Chrono-arm B was definitively more cost-effective than standard flat-arm A treatment since it made the outcome of treatment more effective; there was greater tumor response rate and longer time to progression with less treatment-associated toxicity. Finally, selection of the Melodie brand infusion pump to deliver the chronotherapy resulted in a further 18% reduction of overall costs and made it possible for patients to enjoy increased autonomy and improved quality of life.
4/20/02 Marker rhythms of circadian system function: a study of patients with metastatic colorectal cancer and good performance status Chronobiol Int 2002 Jan;19(1):141-55 PMID: 11962672 Significant individual 24h rhythms were displayed in melatonin by 15 patients, cortisol by seven patients, lymphocytes by five patients, and prominent circadian rhythms in activity were displayed by 10 patients; only one patient exhibited significant rhythms in all the variables. The results suggest the rhythms of melatonin, cortisol, lymphocytes, and rest/activity reflect different components of the circadian system, which may be altered differently during cancer processes. Such 24h rhythm alterations appeared to be independent of conventional clinical factors

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