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Lichterman JN, Reddy SM. Mast Cells: A New Frontier for Cancer Immunotherapy. Cells 2021; 10:cells10061270. [PMID: 34063789 PMCID: PMC8223777 DOI: 10.3390/cells10061270] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/13/2021] [Accepted: 05/19/2021] [Indexed: 12/24/2022] Open
Abstract
Mast cells are unique tissue-resident immune cells of the myeloid lineage that have long been implicated in the pathogenesis of allergic and autoimmune disorders. More recently, mast cells have been recognized as key orchestrators of anti-tumor immunity, modulators of the cancer stroma, and have also been implicated in cancer cell intrinsic properties. As such, mast cells are an underrecognized but very promising target for cancer immunotherapy. In this review, we discuss the role of mast cells in shaping cancer and its microenvironment, the interaction between mast cells and cancer therapies, and strategies to target mast cells to improve cancer outcomes. Specifically, we address (1) decreasing cell numbers through c-KIT inhibition, (2) modulating mast cell activation and phenotype (through mast cell stabilizers, FcεR1 signaling pathway activators/inhibitors, antibodies targeting inhibitory receptors and ligands, toll like receptor agonists), and (3) altering secreted mast cell mediators and their downstream effects. Finally, we discuss the importance of translational research using patient samples to advance the field of mast cell targeting to optimally improve patient outcomes. As we aim to expand the successes of existing cancer immunotherapies, focused clinical and translational studies targeting mast cells in different cancer contexts are now warranted.
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Affiliation(s)
- Jake N. Lichterman
- Division of Hematology/Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
| | - Sangeetha M. Reddy
- Division of Hematology/Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Correspondence: ; Tel.: +1-214-648-4180
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Old wine in new bottles: Drug repurposing in oncology. Eur J Pharmacol 2020; 866:172784. [DOI: 10.1016/j.ejphar.2019.172784] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 11/05/2019] [Accepted: 11/07/2019] [Indexed: 02/07/2023]
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The Effect of Perioperative Cimetidine Administration on Time to Colorectal Cancer Recurrence. Am J Ther 2018; 25:e405-e411. [PMID: 29630589 DOI: 10.1097/mjt.0000000000000547] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Studies have reported that the perioperative use of cimetidine, a histamine type 2 receptor antagonist, in addition to chemotherapy in patients with lymph node-positive colorectal cancer (CRC) improves the survival. STUDY QUESTION To determine if time to CRC recurrence could be prolonged with cimetidine. STUDY DESIGN Cimetidine was prescribed to American Joint on Cancer Committee (AJCC) stage III CRC patients perioperatively. Tumor recurrence was defined as the time (in days) between tumor resection and CRC recurrence. Medical charts of patients diagnosed with CRC between 1996 and 2006 were reviewed. Inclusion criteria were patients with (a) AJCC stage III CRC, (b) who had undergone surgical resection of the tumor, and (c) who received chemotherapy (5-fluorouracil). MEASURES AND OUTCOMES AJCC stage III CRC patients who did and did not receive cimetidine as part of the treatment regimen were compared with respect to their clinical outcomes using univariate analysis and Kaplan-Meier modeling. RESULTS Between 1996 and 2006, 38 patients met our inclusion criteria. Twenty-six percent (10/38) received perioperative cimetidine (mean daily dose, 750 mg; mean duration, 369 days; mean total cumulative cimetidine dose, 274,070 mg/d) in addition to chemotherapy. Time to recurrence and cancer deaths were prolonged in the chemotherapy plus cimetidine group compared with the group that received chemotherapy alone (mean ± SD: 1078 ± 290 vs. 446 ± 62; P = 0.03). In addition, we found a significant positive relationship between the duration of cimetidine therapy (days) and survival duration (correlation coefficient = 0.94, P = 0.02) and time until cancer recurrence (correlation coefficient = 0.99, P = 0.04). Moreover, there was a significant positive relationship between the total cumulative cimetidine dose and survival duration (correlation coefficient = 0.92, P = 0.03). CONCLUSIONS Prolonged duration of cimetidine may be superior to shorter courses in prolonging recurrence of CRC and thus survival.
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Faustino-Rocha AI, Ferreira R, Gama A, Oliveira PA, Ginja M. Antihistamines as promising drugs in cancer therapy. Life Sci 2017; 172:27-41. [DOI: 10.1016/j.lfs.2016.12.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 12/11/2016] [Accepted: 12/13/2016] [Indexed: 12/28/2022]
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Cimetidine-induced Leydig cell apoptosis and reduced EG-VEGF (PK-1) immunoexpression in rats: Evidence for the testicular vasculature atrophy. Reprod Toxicol 2015; 57:50-8. [DOI: 10.1016/j.reprotox.2015.05.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Revised: 05/13/2015] [Accepted: 05/15/2015] [Indexed: 01/09/2023]
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Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP. Repurposing drugs in oncology (ReDO)-cimetidine as an anti-cancer agent. Ecancermedicalscience 2014; 8:485. [PMID: 25525463 PMCID: PMC4268104 DOI: 10.3332/ecancer.2014.485] [Citation(s) in RCA: 197] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Indexed: 12/19/2022] Open
Abstract
Cimetidine, the first H2 receptor antagonist in widespread clinical use, has anti-cancer properties that have been elucidated in a broad range of pre-clinical and clinical studies for a number of different cancer types. These data are summarised and discussed in relation to a number of distinct mechanisms of action. Based on the evidence presented, it is proposed that cimetidine would synergise with a range of other drugs, including existing chemotherapeutics, and that further exploration of the potential of cimetidine as an anti-cancer therapeutic is warranted. Furthermore, there is compelling evidence that cimetidine administration during the peri-operative period may provide a survival benefit in some cancers. A number of possible combinations with other drugs are discussed in the supplementary material accompanying this paper.
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Affiliation(s)
- Pan Pantziarka
- Anticancer Fund, Brussels, 1853 Strombeek-Bever, Belgium ; The George Pantziarka TP53 Trust, London KT1 2JP, UK
| | | | - Lydie Meheus
- Anticancer Fund, Brussels, 1853 Strombeek-Bever, Belgium
| | | | - Vikas P Sukhatme
- GlobalCures, Inc; Newton MA 02459, USA ; Beth Israel Deaconess Medical Centre and Harvard Medical School, Boston, MA 02215, USA
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The impact of anti-inflammatory agents on the outcome of patients with colorectal cancer. Cancer Treat Rev 2014; 40:68-77. [DOI: 10.1016/j.ctrv.2013.05.006] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Revised: 05/21/2013] [Accepted: 05/23/2013] [Indexed: 01/01/2023]
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Deva S, Jameson M. Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal cancer. Cochrane Database Syst Rev 2012; 2012:CD007814. [PMID: 22895966 PMCID: PMC11627143 DOI: 10.1002/14651858.cd007814.pub2] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Anecdotal reports of tumour regression with histamine type 2 receptor antagonists (H(2)RAs) have lead to a series of trials with this class of drug as adjuvant therapy to try and improve outcomes in patients with resected colorectal cancers. There was a plausible scientific rationale suggesting merit in this strategy. This included improved immune surveillance (by way of increasing tumour infiltrating lymphocytes), inhibiting the direct proliferative effect of histamine as a growth factor for colorectal cancer and, in the case of cimetidine, inhibiting endothelial expression of E-selectin (a cell adhesion molecule thought to be critical for metastatic spread). OBJECTIVES To determine if H(2)RAs improve overall survival when used as pre- and/or postoperative therapy in colorectal cancer patients who have had surgical resection with curative intent. We also stratified the results to see if there was an improvement in overall survival in terms of the specific H(2)RA used. SEARCH METHODS Randomised controlled trials were identified using a sensitive search strategy in the following databases: MEDLINE (1964 to present), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2009), EMBASE (1980 to present) and Cancerlit (1983 to present). SELECTION CRITERIA Criteria for study selection included: patients with colorectal cancer surgically resected with curative intent; H(2)RAs used i) at any dose, ii) for any length of time, iii) with any other treatment modality and iv) in the pre-, peri- or post-operative period. The results were stratified for the H(2)RA used. DATA COLLECTION AND ANALYSIS The literature search retrieved 142 articles. There were six studies included in the final analysis, published from 1995 to 2007, including a total of 1229 patients. All patients were analysed by intention to treat according to their initial allocation. Log hazard ratios and standard errors of treatment effects (on overall survival) were calculated using the Cochrane statistical package RevMan Version 5. Hazard ratios and standard errors were recorded from trial publications or, if not provided, were estimated from published actuarial survival curves using a spreadsheet designed for this purpose (http://www.biomedcentral.com/content/supplementary/1745-6215-8-16-S1.xls). MAIN RESULTS Of the six identified trials, five used cimetidine as the experimental H(2)RA, whereas one used ranitidine. There was a trend towards improved survival when H(2)RAs were utilised as adjuvant therapy in patients having curative-intent surgery for colorectal cancer (HR 0.70; 95% CI 0.48-1.03, P = 0.07). Analysis of the five cimetidine trials (n = 421) revealed a statistically significant improvement in overall survival (HR 0.53; 95% CI 0.32 to 0.87). AUTHORS' CONCLUSIONS Of the H(2)RAs evaluated cimetidine appears to confer a survival benefit when given as an adjunct to curative surgical resection of colorectal cancers. The trial designs were heterogeneous and adjuvant therapy has evolved since these trials were performed. Further prospective randomised studies are warranted.
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Affiliation(s)
- Sanjeev Deva
- Cancer and Blood, AucklandHospital, Auckland, New Zealand.
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Kubecova M, Kolostova K, Pinterova D, Kacprzak G, Bobek V. Cimetidine: An anticancer drug? Eur J Pharm Sci 2011; 42:439-44. [DOI: 10.1016/j.ejps.2011.02.004] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2010] [Revised: 12/14/2010] [Accepted: 02/08/2011] [Indexed: 10/18/2022]
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Sato H, Usuda N, Kuroda M, Hashimoto S, Maruta M, Maeda K. Significance of Serum Concentrations of E-selectin and CA19-9 in the Prognosis of Colorectal Cancer. Jpn J Clin Oncol 2010; 40:1073-80. [DOI: 10.1093/jjco/hyq095] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
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Takagaki K, Osawa S, Horio Y, Yamada T, Hamaya Y, Takayanagi Y, Furuta T, Hishida A, Ikuma M. Cytokine responses of intraepithelial lymphocytes are regulated by histamine H(2) receptor. J Gastroenterol 2009; 44:285-96. [PMID: 19277450 DOI: 10.1007/s00535-009-0019-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2007] [Accepted: 12/06/2008] [Indexed: 02/04/2023]
Abstract
BACKGROUND Histamine participates in the immune regulation of several gastrointestinal diseases. However, the effect of histamine on intestinal intraepithelial lymphocytes (IELs), the front line of the intestinal mucosal immune system, is not well understood. We examined whether histamine has a direct effect on cytokine production by IELs and the involvement of histamine receptor subtypes. METHODS Murine IELs were activated by PMA plus ionomycin with/without histamine. Secreted cytokines were measured and compared with those of splenocytes. Intracellular cytokines were detected by flow cytometry. Expression of histamine receptor subtypes in IELs was examined by RT-PCR. RESULTS Histamine H(1) receptor (H(1)R), H(2)R, and H(4)R, but not H(3)R mRNA were expressed on IELs. Histamine significantly decreased Th1-cytokine (IFN-gamma, TNF-alpha, and IL-2) and also IL-4 production in IELs as well as splenocytes. The selective H(2)R antagonist famotidine, but not the H(1)R antagonist pyrilamine nor the H(3)R/H(4)R antagonist thioperamide, competes with the inhibitory effect of histamine on these cytokine production in IELs. These suppressive effects of histamine were mimicked by a selective H(2)R/H(4)R agonist dimaprit. Further, these suppressive effects of histamine for Th1-cytokine and IL-4 did not accompany the enhancement of IL-10 production or IL-10 mRNA level in IELs. Intracellular cytokine analysis revealed that the number of IFN-gamma-producing alphabeta T cells was significantly reduced by histamine in IELs. CONCLUSIONS Histamine has a direct suppressive effect on IEL-derived cytokines via H(2)R, which would have a crucial role in the suppression of local immunoregulation in the intestinal epithelium.
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Affiliation(s)
- Kosuke Takagaki
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
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Abstract
BACKGROUND Colon cancer is potentially curable by surgery. Although adjuvant chemotherapy benefits patients with stage III disease, there is uncertainty of such benefit in stage II colon cancer. A systematic review of the literature was performed to better define the potential benefits of adjuvant therapy for patients with stage II colon cancer. OBJECTIVES To determine the effects of adjuvant therapy on overall survival and disease-free survival in patients with stage II colon cancer. SEARCH STRATEGY Ovid MEDLINE (1986-2007), EMBASE (1980-2007), and EBM Reviews - Cochrane Central Register of Controlled Trials ( to 2007) were searched using the medical headings "colonic neoplasms", "colorectal neoplasms", "adjuvant chemotherapy", "adjuvant radiotherapy" and "immunotherapy", and the text words "colon cancer" and "colonic neoplasms". In addition, proceedings from the annual meetings of the American Society of Clinical Oncology and the European Society of Medical Oncology (1996 to 2004) as well as personal files were searched for additional information. SELECTION CRITERIA Randomized trials or meta-analyses containing data on stage II colon cancer patients undergoing adjuvant therapy versus surgery alone. DATA COLLECTION AND ANALYSIS :Three reviewers summarized the results of selected studies. The main outcomes of interest were overall and disease-free survival, however, data on toxicity and treatment delivery were also recorded. MAIN RESULTS With regards to the effect of adjuvant therapy on stage II colon cancer, the pooled relative risk ratio for overall survival was 0.96 (95% confidence interval 0.88, 1.05). With regards to disease-free survival, the pooled relative risk ratio was 0.83 (95% confidence interval 0.75, 0.92). AUTHORS' CONCLUSIONS Although there was no improvement in overall survival in the pooled analysis, we did find that disease-free survival in patients with stage II colon cancer was significantly better with the use of adjuvant therapy. It seems reasonable to discuss the benefits of adjuvant systemic chemotherapy with those stage II patients who have high risk features, including obstruction, perforation, inadequate lymph node sampling or T4 disease. The co-morbidities and likelihood of tolerating adjuvant systemic chemotherapy should be considered as well. There exists a need to further define which high-risk features in stage II colon cancer patients should be used to select patients for adjuvant therapy. Also, researchers must continue to search for other therapies which might be more effective, shorter in duration and less toxic than those available today.
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Affiliation(s)
- Alvaro Figueredo
- Hamilton Regional Cancer Centre, McMaster Univ., Dept. of Clin. Epid. and Stat.,, 699 Concession Street, Hamilton, Ontario, Canada, L8V 5C2.
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Jiang CG, Li JB, Xu HM, Yu M, Wu T, Liu FR. Effect of cimetidine on the proliferation and apoptosis of human gastric cancer cell line SGC-7901. Shijie Huaren Xiaohua Zazhi 2007; 15:118-122. [DOI: 10.11569/wcjd.v15.i2.118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of cimetidine on the proliferation and apoptosis of human gastric cancer cell line SGC-7901 and its related mechanism.
METHODS: Human gastric cancer cell SGC-7901 was cultivated by routine method, then treated with different concentrations of cimetidine. The proliferation of SGC-7901 cells was examined by MTT assay, and the cell cycle and apoptosis were detected by flow cytometry. After Hoechst33258 staining, the morphologic changes of SGC-7901 cells were observed under fluorescence microscope, and the ultrastructure of the cells was investigated by transmission electron microscopy. The levels of Bcl-2 and Bax protein expression were detected by Western blot analysis.
RESULTS: After dealing with cimetidine (0.5, 1, 2.5, 5, 10 mmol/L) for 24 and 48 hours, we found that cimetidine significantly inhibited the proliferation of SGC-7901 cells in a time- and concentration-dependent manner (24 h: 0.705 ± 0.018, 0.560 ± 0.038, 0.408 ± 0.029, 0.276 ± 0.042, 0.205 ± 0.031 vs 0.803 ± 0.012, P < 0.05; 48 h: 0.902 ± 0.024, 0.671 ± 0.015, 0.420 ± 0.030, 0.180 ± 0.037, 0.117 ± 0.021 vs 1.079 ± 0.040, P < 0.05), whereas there was no significant cytotoxic effect as the concentration was below 0.25 mmol/L. cimetidine at the concentrations of 0.5, 1, 2.5, 5, and 10 mmol/L induced typical apoptosis of SGC-7901 cells, and flow cytometry showed an apoptosis peak. The percentage of G0/G1-phase cells was significantly increased (60.83% ± 2.27%, 67.21% ± 1.18%, 75.15% ± 4.01%, 81.88% ± 3.10%, 86.99% ± 1.43% vs 50.28% ± 1.97%, P < 0.05). The expression of Bcl-2 protein was decreased while that of Bax protein was increased following cimetidine treatment.
CONCLUSION: Cimetidine may inhibit the proliferation of SGC-7901 cells through inducing cell apoptosis and cell cycle arrest.
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Abstract
BACKGROUND Advances in immunology and molecular biology have shown that colorectal cancer is potentially immunogenic and that host immune responses influence survival. However, immune surveillance and activation is frequently ineffective in preventing and/or controlling tumour growth. AIM To discuss potential ways in which colorectal cancer induces immune suppression, its effect upon prognosis and avenues for therapeutic development. METHOD A literature review was undertaken for evidence of colorectal cancer-induced immune suppression using PubMed and Medline searches. Further studies were identified from the reference lists of identified papers. RESULTS Immune suppression occurs at a molecular and cellular level and can result in a shift from cellular to humoral immunity. Several mechanisms for immune suppression have been described affecting innate and adaptive immunity with suppression linked to poorer clinical outcome. CONCLUSIONS Colorectal cancer causes direct inhibition of the host's immune response with a detrimental effect upon prognosis. Immunotherapy offers a therapeutic strategy to counteract these effects with promising results seen particularly in precancerous conditions and early tumours. This review strongly suggests that immunotherapy should be incorporated into adjuvant therapeutic trials for stage 2 tumours and be considered as adjuvant treatment in conjunction with standard chemotherapy regimes for advanced disease.
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Affiliation(s)
- C Evans
- Institution Colorectal Surgery Unit & Division of Oncology, St George's Hospital, Blackshaw Road, London, UK
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Kapoor S, Pal S, Sahni P, Dattagupta S, Kanti Chattopadhyay T. Effect of Pre-Operative Short Course Famotidine on Tumor Infiltrating Lymphocytes in Colorectal Cancer: A Double Blind, Placebo Controlled, Prospective Randomized Study. J Surg Res 2005; 129:172-5. [PMID: 15882879 DOI: 10.1016/j.jss.2005.02.030] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2005] [Revised: 02/27/2005] [Accepted: 02/28/2005] [Indexed: 10/25/2022]
Abstract
BACKGROUND Pilot studies have shown that histamine H2 receptor antagonists augment the natural immunity against cancer in colorectal and gastric cancer by enhancing lymphocytic infiltration in the tumors. However, a study of adjuvant ranitidine failed to show a significant benefit in colorectal cancer, possibly because of the immunosuppression exerted by blood transfusion and post-operative infections. The pre-operative use of H2 receptor antagonists may therefore be of greater benefit. Except for a pilot study using cimetidine, there are no trials that have evaluated the effect of pre-operative H2 receptor antagonists on tumor infiltrating lymphocytes in colorectal cancer. OBJECTIVE To evaluate the efficacy of famotidine in augmenting tumor infiltrating lymphocytes in colorectal cancer. STUDY DESIGN Double blind, placebo controlled, prospective randomized study. METHODS Twenty-three patients with resectable colorectal cancer were randomized to receive famotidine (n = 11) or placebo (n = 12). Famotidine was given for 1 week pre-operatively in a dose of 40 mg per day p.o. After resection, the specimens were analyzed histologically for lymphocytic infiltration by a pathologist blinded to the two groups. Lymphocytic infiltration more than 50 cells per high power field, involving more than 50% of the tumor-normal tissue interface was considered significant. RESULTS The two groups were comparable for age, gender, pre-operative carcino embryonic antigen (CEA) levels and pathological stage. Significant lymphocytic infiltration was seen in 63.6% (7 of 11) patients in the study group compared to only 8.5% (1 of 12) patients in the placebo group (P = 0.005). Despite fewer recurrences and a longer survival in the study group, the difference was not significant. CONCLUSION This study shows that pre-operative famotidine may significantly enhance lymphocytic infiltration in colorectal cancer and may have potential for use as an anticancer agent in colorectal cancer.
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Affiliation(s)
- Sorabh Kapoor
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India.
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Lin CY, Bai DJ, Yuan HY, Wang K, Yang GL, Hu MB, Wu ZQ, Li Y. Perioperative cimetidine administration promotes peripheral blood lymphocytes and tumor infiltrating lymphocytes in patients with gastrointestinal cancer: Results of a randomized controlled clinical trial. World J Gastroenterol 2004; 10:136-42. [PMID: 14695785 PMCID: PMC4717066 DOI: 10.3748/wjg.v10.i1.136] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To study the effects of perioperative administration of cimetidine (CIM) on peripheral blood lymphocytes, natural killer (NK) cells and tumor infiltrating lymphocytes (TIL) in patients with gastrointestinal (GI) cancer.
METHODS: Forty-nine GI cancer patients were randomized into treatment group, who took CIM in perioperative period, and control group, who did not take the drug. The treatment was initiated 7 days before operation and continued for 10 days after surgery. At baseline examination before operation, on the 2nd and 10th postoperative days, total T lymphocytes, T helper cells, T suppressor cells, and NK cells in peripheral blood were measured respectively by immunocytochemical method using mouse-anti human CD3, CD4, CD8 and CD57 monoclonal antibodies. Blood samples from 20 healthy volunteers were treated in the same way as normal controls. Surgical specimens were examined during routine histopathological evaluation for the presence of TIL in tumor margin. Immunohistochemical study was performed to measure the proportion of T and B lymphocytes in TIL population. T and B lymphocytes were detected respectively using mouse-anti-human CD3 and CD20 monoclonal antibodies.
RESULTS: In comparison with normal controls, both the treatment and control groups had decreased T cells, T helper cells and NK cells at baseline. In control group, total T cells, T helper cells and NK cells declined continuously with the disease progression and the decrease became more obvious after operation. From baseline to the 2nd postoperative day, the proportion of total T cells, T helper cells, and NK cells went down from 60.5 ± 4.6% to 56.2 ± 3.8%, 33.4 ± 3.7% to 28.1 ± 3.4%, and 15.0 ± 2.8% to 14.2 ± 2.2%, respectively. On the other hand, there were significant improvements in these parameters after CIM treatment. On the 10th postoperative day, the treatment group had significantly higher percentages of total T cells, T helper cells and NK cells than control group. Moreover, CIM treatment also boosted TIL response, as was reflected by findings that 68%(17/25) of the patients in treatment group had significant TIL responses and only 25% (6/24) of the cases had discernible TIL responses (P < 0.01).
CONCLUSION: Perioperative application of CIM to GI cancer patients could help restore the diminished cellular immunity induced by tumor burden and surgical maneuver. The drug could also boost TIL responses to tumor. These effects suggest that the drug be used as an immunomodulator for GI cancer patients.
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Affiliation(s)
- Cong-Yao Lin
- Department of Oncology, Zhongnan Hospital of Wuhan University, 169 Dong Hu Rd, Wuhan 430073, Hubei Province, China.
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Takahashi K, Tanaka S, Furuta K, Ichikawa A. Histamine H(2) receptor-mediated modulation of local cytokine expression in a mouse experimental tumor model. Biochem Biophys Res Commun 2002; 297:1205-10. [PMID: 12372415 DOI: 10.1016/s0006-291x(02)02360-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Accumulating evidence indicates that histamine is involved in the modulation of cytokine expression patterns. We previously reported that daily treatment with the H(2) receptor antagonist, cimetidine, suppressed tumor growth through alteration of the local cytokine expression pattern. In this study, we used a mouse strain genetically lacking histidine decarboxylase (HDC), to evaluate the role of endogenous histamine synthesis on cytokine expression and tumor development. In the mutant mice, cimetidine had no effect on tumor growth, whereas an H(2) agonist, dimaprit, significantly enhanced tumor growth. When the HDC-deficient mice were implanted with mutant CT-26 cells stably expressing HDC, drastic suppression of tumor growth by cimetidine was observed, which was accompanied by augmentation of mRNA expression of LT-beta, TNF-alpha, and IFN-gamma in the tumor tissues. These results suggest that endogenous histamine synthesis in tumor tissues suppresses local tumor immunity via the H(2) receptors, resulting in tumor growth promotion.
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Affiliation(s)
- Kohji Takahashi
- Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, 606-8501, Kyoto, Japan
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La Vecchia C, Tavani A. A review of epidemiological studies on cancer in relation to the use of anti-ulcer drugs. Eur J Cancer Prev 2002; 11:117-23. [PMID: 11984128 DOI: 10.1097/00008469-200204000-00002] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
H2-receptor antagonists have been widely used since the late 1970s for the treatment of gastrointestinal ulcers and other benign conditions of the stomach, oesophagus and duodenum. Several case reports suggested that long-term therapy with H2-receptor antagonists, mainly cimetidine and ranitidine, might increase the risk of gastric cancer. After early case reports, at least six analytical epidemiological studies (two cohort and four case-control) were published, including a total of about 1000 cases of gastric cancer. The relative risks (RR) were systematically and substantially elevated in the first year since starting H2-receptor antagonist use, and levelled off in the following years. Some excess risk was still apparent during the first 5 years of drug use, probably due to incorrect diagnosis and treatment of pre-existing neoplastic gastric lesions, but the estimated RR was not above unity for > or = 10 years since starting drug treatment in the two studies including information on long-term use. The findings of analytical epidemiological studies are thus consistent with the absence of a causal association between H2-receptor antagonist use and gastric cancer risk. Data on oesophageal and colorectal cancer do not support a relevant relation between cimetidine use and the risk of these neoplasms. With reference to total cancer mortality, in a Danish cohort study, for males the RR was 1.9 in the first year, and 1.4 in the first 5 years; corresponding values for females were 1.7 and 1.5. In a British cohort study, the RR was 3.4 in the first year, and 1.3 in the years 2-10. The excess risk in the first year was essentially due to gastric cancer. Post-marketing surveillance data for omeprazole and other proton pump inhibitors are much scantier than for H2-receptor antagonists, particularly on long-term use.
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Affiliation(s)
- C La Vecchia
- Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
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Matsumoto S, Imaeda Y, Umemoto S, Kobayashi K, Suzuki H, Okamoto T. Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells. Br J Cancer 2002; 86:161-7. [PMID: 11870500 PMCID: PMC2375187 DOI: 10.1038/sj.bjc.6600048] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2001] [Revised: 10/24/2001] [Accepted: 11/01/2001] [Indexed: 11/09/2022] Open
Abstract
Cimetidine has been shown to have beneficial effects in colorectal cancer patients. In this study, a total of 64 colorectal cancer patients who received curative operation were examined for the effects of cimetidine treatment on survival and recurrence. The cimetidine group was given 800 mg day(-1) of cimetidine orally together with 200 mg day(-1) of 5-fluorouracil, while the control group received 5-fluorouracil alone. The treatment was initiated 2 weeks after the operation and terminated after 1 year. Robust beneficial effects of cimetidine were noted: the 10-year survival rate of the cimetidine group was 84.6% whereas that of control group was 49.8% (P<0.0001). According to our previous observations that cimetidine blocked the expression of E-selectin on vascular endothelium and inhibited the adhesion of cancer cells to the endothelium, we have further stratified the patients according to the expression levels of sialyl Lewis antigens X (sL(x)) and A (sL(a)). We found that cimetidine treatment was particularly effective in patients whose tumour had higher sL(x) and sL(a) antigen levels. For example, the 10-year cumulative survival rate of the cimetidine group with higher CSLEX staining, recognizing sL(x), of tumours was 95.5%, whereas that of control group was 35.1% (P=0.0001). In contrast, in the group of patients with no or low levels CSLEX staining, cimetidine did not show significant beneficial effect (the 10-year survival rate of the cimetidine group was 70.0% and that of control group was 85.7% (P=n.s.)). These results clearly indicate that cimetidine treatment dramatically improved survival in colorectal cancer patients with tumour cells expressing high levels of sL(x) and sL(a).
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Affiliation(s)
- S Matsumoto
- Department of Surgery, Second Teaching Hospital, School of Medicine, Fujita Health University, 3-6-10 Otohbashi, Nakagawa-ku, Nagoya 454-8509, Japan.
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Eaton D, Hawkins RE. Cimetidine in colorectal cancer--are the effects immunological or adhesion-mediated? Br J Cancer 2002; 86:159-60. [PMID: 11870499 PMCID: PMC2375193 DOI: 10.1038/sj.bjc.6600097] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
British Journal of Cancer (2002) 86, 159–160. DOI: 10.1038/sj/bjc/6600097www.bjcancer.com © 2002 The Cancer Research Campaign
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Muñoz Gómez M, Llau Pitarch JV, Leal Noval SR, García Erce JA, Culebras Fernández JM. Transfusión sanguínea perioperatoria en el paciente neoplásico (II). Alternativas para la reducción de los riesgos transfusionales. Cir Esp 2002. [DOI: 10.1016/s0009-739x(02)72070-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Takahashi K, Tanaka S, Ichikawa A. Effect of cimetidine on intratumoral cytokine expression in an experimental tumor. Biochem Biophys Res Commun 2001; 281:1113-9. [PMID: 11243850 DOI: 10.1006/bbrc.2001.4487] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
To evaluate the immunomodulatory effects of histamine in vivo, we analyzed an experimental syngenic tumor model using a colon adenocarcinoma cell line, CT-26, in Balb/c mice. In this model, distinct tumor growth was observed around 6 days after inoculation. Daily administration of cimetidine (0.12 mg/kg/day) significantly suppressed the increases in tumor volume and weight. On day 6 and day 7, histidine decarboxylase (HDC) activity was markedly increased. To examine the alterations in the local immune system, the cytokine expressions in the tumor tissue were measured by ribonuclease protection assay. The cytokine expression levels such as lymphotoxin-beta, tumor necrosis factor-alpha, interferon-gamma, interleukin-10, and interleukin-15 were considerably lower in tissues on day 14 than those on day 6. These decreased expressions were all restored by cimetidine. These results indicated that the effects of cimetidine on tumor growth in this model might be mediated by restoration of the decreased local cytokine expression, which exerts antitumoral effects.
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Affiliation(s)
- K Takahashi
- Department of Physiological Chemistry, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan
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Li Y, Yang GL, Yuan HY, Bai DJ, Wang K, Wang Y. Effects of perioperative cimetidine administration on tumor cell nuclear morphometry and DNA content in patients with gastrointestinal cancer. Chin J Cancer Res 2000. [DOI: 10.1007/bf02983445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Yip D, Strickland AH, Karapetis CS, Hawkins CA, Harper PG. Immunomodulation therapy in colorectal carcinoma. Cancer Treat Rev 2000; 26:169-90. [PMID: 10814560 DOI: 10.1053/ctrv.1999.0160] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
There has been much progress in the understanding of the relationship between the immune system and colorectal cancer. This has led to the use of immunomodulatory therapy in the adjuvant and palliative treatment of the condition. Although attempts at the use of non-specific immunomodulation with agents such as levamisole, cimetidine, alpha interferon and Bacillus Calmette-Guerin (BCG) have not produced significant clinical benefits when tested in randomized trials in both the adjuvant setting and for metastatic disease, promising results are being obtained with more specific therapy. Edrecolomab [corrected], a murine monoclonal antibody targeting the 17-1A antigen on malignant colorectal cells has produced a reduction in relapse and mortality rates when used as adjuvant treatment following surgery for Dukes' C colon cancer. Active specific therapy with autologous tumour vaccine administered with BCG has produced similar benefits in Dukes' B cancer. Both 3H1 anti-idiotypic antibody against carcinoembryonic antigen and 105AD7 antibody to gp72 glycoprotein have demonstrated in-vitro and in-vivo immune activation against tumour. Non-randomized studies postulate prolongation of survival using these antibodies in advanced disease. These agents are all currently being tested in randomized studies powered to detect meaningful survival differences and clinical benefit. Immune therapy offers the potential of low toxicity therapy in colorectal cancer and may have a role as an adjunct to conventional chemotherapy.
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Affiliation(s)
- D Yip
- Department of Medical Oncology, Guy's Hospital, St Thomas St, London, UK
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Abstract
Several clinical trials have now been carried out with histamine type 2 receptor antagonists in cancer patients often as an adjunct to surgical resection of the primary tumour While promising results have been obtained in some groups of patients with gastrointestinal cancer, with increased survival and evidence of increased immunological recognition of tumour, results are less encouraging for breast cancer. This may be due to differences in the levels of histamine or the role of histamine in growth of these different tumour types.
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Affiliation(s)
- E Bolton
- University of New South Wales, Department of Surgery, St George Hospital, Sydney, Australia
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Langman MJ, Dunn JA, Whiting JL, Burton A, Hallissey MT, Fielding JW, Kerr DJ. Prospective, double-blind, placebo-controlled randomized trial of cimetidine in gastric cancer. British Stomach Cancer Group. Br J Cancer 1999; 81:1356-62. [PMID: 10604733 PMCID: PMC2362962 DOI: 10.1038/sj.bjc.6690457] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Cimetidine is thought to inhibit suppressor T-lymphocyte function and preliminary evidence from a randomized trial indicated that it might prolong survival for patients with operable and inoperable gastric cancer. The British Stomach Cancer Group conducted a randomized, double-blind, placebo-controlled trial examining the effects of cimetidine (400 mg or 800 mg twice a day) on the survival of patients with early (stages I, II and III: n = 229) and advanced (stages IVa and IVb: n = 201) gastric cancer. The primary end point was death. A total of 442 patients were randomized by 59 consultants in 39 hospitals between February 1990 and March 1995. Log-rank survival analysis was used to assess differences between the groups. Three hundred and forty patients died during the study: 166 (49%) in the cimetidine treatment groups and 174 (51%) in the placebo groups. Median survival for patients receiving cimetidine was 13 months (95% confidence interval (CI) 9-16 months) and 11 months in the placebo arm (95% CI 9-14 months). There was no significant difference in survival between the two treatment groups (P = 0.42) or between different doses of cimetidine tablets (P = 0.46). Five-year survival of those patients randomized to cimetidine was 21% compared to 18% for those patients randomized to placebo. Cimetidine at a dose of 400 mg or 800 mg twice a day does not have a significant influence on the survival of patients with gastric cancer compared to placebo.
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Affiliation(s)
- M J Langman
- Department of Medicine, CRC Institute for Cancer Studies, Clinical Research Block, The Medical School, Edgbaston, Birmingham, UK
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Kelly MD, King J, Cherian M, Dwerryhouse SJ, Finlay IG, Adams WJ, King DW, Lubowski DZ, Morris DL. Randomized trial of preoperative cimetidine in patients with colorectal carcinoma with quantitative assessment of tumor-associated lymphocytes. Cancer 1999; 85:1658-63. [PMID: 10223557 DOI: 10.1002/(sici)1097-0142(19990415)85:8<1658::aid-cncr3>3.0.co;2-q] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Previous studies have suggested that cimetidine, a histamine-2 receptor antagonist with immunostimulatory effects, may improve survival in patients with colorectal carcinoma. This effect may be apparent by an increase in the number of peritumoral lymphocytes. A prospective, double blind, randomized, placebo-controlled trial of a short course of preoperative treatment with cimetidine in patients with colorectal carcinoma was performed to assess the effect of cimetidine on survival and on the number of peritumoral lymphocytes. METHODS One hundred and twenty-five patients who were scheduled to undergo elective colon or rectal excision for carcinoma were randomized to receive either placebo or cimetidine preoperatively for 5 days. In addition to standard histopathology, immunohistochemistry and computer video image analysis were used to assess the number of peritumoral lymphocytes in an objective manner. Interim survival analysis according to the Kaplan-Meier method was performed. RESULTS A trend toward a survival advantage in the group of patients receiving cimetidine (800 mg twice daily) compared with the placebo group was observed (P = 0.20, log rank test) that was most marked in patients with replication error negative tumors (P = 0.04). Similarly, in these two groups there was a trend toward an increase in the number of patients with a conspicuous lymphocytic infiltration (P = 0.10, chi-square test). However, there was no difference in the number of peritumoral lymphocytes as measured by image analysis. CONCLUSIONS Based on the results of the current study, a short course of preoperative treatment with cimetidine does appear to have an effect on patient survival; however, the exact mechanism is unknown. The failure of this study to demonstrate a clear increase in the local lymphocyte response does not exclude an immunologic mechanism of action.
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Affiliation(s)
- M D Kelly
- Department of Surgery, University of New South Wales St. George Hospital, Sydney, Australia
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Tavani A, Fioretti F, Franceschi S, La Vecchia C. Pilot study--cimetidine enhances lymphocyte infiltration of human colorectal carcinoma: results of a small randomized control trial. Cancer 1998; 82:2296-7. [PMID: 9610714 DOI: 10.1002/(sici)1097-0142(19980601)82:11<2296::aid-cncr31>3.0.co;2-n] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Abstract
BACKGROUND Histamine inhibits lymphocyte function in vitro at concentrations of greater than 10(-6) mol/l. The aim of this study was to determine whether histamine concentrations in breast cancers were sufficient to produce an immunological effect. METHODS Tumour and adjacent normal breast content of histamine was measured using a radioenzymatic assay in 29 patients having surgery for breast cancer. RESULTS The median content of histamine in breast cancer tissue was 5.4 (range 0.9-27.3) microg/g (median concentration 4.5 x 10(-5) mol/l), and was significantly greater than that in adjacent breast tissue (P = 0.007). CONCLUSION The concentration of histamine in breast cancer was sufficient to inhibit lymphocyte function and could be locally immunosuppressive.
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Affiliation(s)
- J L Reynolds
- Department of Surgery, University of New South Wales, St George Hospital, Kogarah, Australia
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Adams WJ, Morris DL. Pilot study--cimetidine enhances lymphocyte infiltration of human colorectal carcinoma: results of a small randomized control trial. Cancer 1997; 80:15-21. [PMID: 9210704 DOI: 10.1002/(sici)1097-0142(19970701)80:1<15::aid-cncr3>3.0.co;2-e] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cimetidine preserves postoperative immune function and inhibits the growth of some cancers. In this study, the effect of cimetidine on the local immune response to colorectal carcinoma was investigated. METHODS Forty-two patients scheduled for elective resection of colorectal carcinoma were randomized either to receive cimetidine for 1 week perioperatively or to act as controls. A lymphocyte density of 50 cells per high-power field (approximately 50% of the tumor/tissue interface) was considered a positive response. Patient survival was determined by Kaplan-Meier life table analysis. The effects of histamine and cimetidine on normal subject lymphocyte function was determined in a mitogen-stimulated proliferation assay. RESULTS A positive lymphocyte response was observed in 5 of 24 control carcinoma patients (21%) and 10 of 18 cimetidine-treated carcinoma patients (56%) (P = 0.03). The presence of a lymphocyte response correlated with a better survival (P = 0.02). Histamine had an inhibitory effect on lymphocyte proliferation with a median effective dose of 5 x 10(-7) M. Cimetidine antagonized this effect with a negative logarithm of the cimetidine molar concentration required to reduce the effect of histamine in half of 6.55. CONCLUSIONS Histamine inhibits normal lymphocyte function, antagonized by cimetidine at a histamine type 2 receptor. Cimetidine increases lymphocyte infiltration of primary colorectal carcinoma, possibly by overcoming the immunosuppressive effects of high local histamine concentrations. The presence of a local lymphocyte response correlates with an improved 3-year survival.
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Affiliation(s)
- W J Adams
- University of New South Wales Department of Surgery, The St. George Hospital, Kogarah, Australia
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Abstract
Considerable evidence has emerged to suggest that histamine participates in the regulation of the inflammatory response, immune reaction, coagulation cascade, and cardiovascular function. Furthermore, histamine may play a major role in the growth of normal and malignant tissue as a regulator of proliferation and angiogenesis. Specific histamine receptors have been identified on the surface of bone marrow cells, immune competent cells, endothelial cells, fibroblasts, and also on malignant cells. This has prompted research in regulation by specific histamine receptor agonists and antagonists. Results from such studies are currently accumulating and suggest that the histamine-2 receptor antagonists have potential beneficial effects in the treatment of certain malignant, autoimmune and skin diseases, either alone or in combination with other drugs. The beneficial effect of histamine-2 receptor antagonists as adjuvant single drugs to reduce trauma-, blood transfusion- and sepsis-induced immunosuppression has led to research in combined treatment regimens in major surgery, particularly, of patients operated on for malignant diseases.
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Affiliation(s)
- H J Nielsen
- Department of Surgical Gastroenterology, Hvidovre University Hospital, Denmark
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L.Morris D. Reply to “Histamine, cimetidine and colorectal cancer”. Nat Med 1996. [DOI: 10.1038/nm0496-364b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Lawson JA, Adams WJ, Morris DL. Ranitidine and cimetidine differ in their in vitro and in vivo effects on human colonic cancer growth. Br J Cancer 1996; 73:872-6. [PMID: 8611398 PMCID: PMC2074256 DOI: 10.1038/bjc.1996.155] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Histamine has recently been shown to be a growth factor for some gastric and colorectal cancer cells. Previous studies have shown that cimetidine blocks in vitro and in vivo histamine-stimulated growth and cAMP release from the human colonic cancer cell line, C170. In this study, ranitidine, another H2 receptor antagonist, did not affect either basal or histamine-stimulated in vitro proliferation of C170, and failed to prevent cAMP release in vitro. Ranitidine did not inhibit in vivo growth of C170 at a dose of 1, 10, 25, 50 or 100 mg/kg, in contrast to 50 mg/kg/day cimetidine, which produced 39.3% inhibition of tumour volume (p<0.01) after 23 days' treatment. Ranitidine did not inhibit in vivo histamine-stimulated growth of C170 cells . LIM2412, another colonic cancer cell line, was significantly stimulated by both cimetidine and ranitidine in vivo. Ranitidine had no effect on in vitro cell proliferation.
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Affiliation(s)
- J A Lawson
- UNSW Department of Surgery, The St. George Hospital, Kogarah Sydney, Australia
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Affiliation(s)
- D L Morris
- UNSW Department of Surgery, St. George Hospital, Kogarah, Sydney, Australia
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