Augmented natural killer activity in ovarian cancer patients treated with cimetidine

Kikuchi, Yoshihiro; Oomori, Keibun; Kizawa, Isao; Kato, Koichi

doi:10.1016/0277-5379(86)90003-9

Cited by 25 publications

(12 citation statements)

References 16 publications

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“…[15][16][17][18][19][20][21] Our current data confirm that PBMCs from patients with advanced ovarian carcinoma show a marked decrease in natural killer cytotoxicity compared with PMBCs from normal subjects, despite having normal proportions of natural killer cells, CD4ϩ T cells, and CD8ϩ T cells. Furthermore, no increases in other lymphocyte populations that exhibit suppressor activity were observed.…”

Section: Discussionsupporting

confidence: 66%

Cisplatin-based polychemotherapy reduces the natural cytotoxicity of peripheral blood mononuclear cells in patients with advanced ovarian carcinoma and their in vitro responsiveness to interleukin-12 incubation

Garzetti

Ciavattini

Muzzioli

et al. 1999

Cancer

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Section: Discussionsupporting

confidence: 66%

Cisplatin-based polychemotherapy reduces the natural cytotoxicity of peripheral blood mononuclear cells in patients with advanced ovarian carcinoma and their in vitro responsiveness to interleukin-12 incubation

Garzetti

Ciavattini

Muzzioli

et al. 1999

Cancer

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“…They have been shown to reduce primary tumor growth [34] and lung metastases [34,35] and inTumor immunotherapy with 1-1-2 receptor antagonists, indomethacin and IL-2 crease survival in tumor-bearing animals [34]. In human cancer patients, H-2RA have been reported to increase IL-2 production [48] and peripheral blood NK activity [31,32] and cause partial/ complete objective responses [36,37]. In several reports, human cancer patients given H-2RA therapy did not respond [49,50].…”

Section: Discussionmentioning

confidence: 99%

“…H-2RA have been shown to stimulate IgM and IgG immunoglobulin and IL-2 production [27], increase the response of lymphocytes to mitogens [28,29], enhance lymphocyte responsiveness in an allogeneic and autologous mixed lymphocyte reaction [30] and restore NK activity in ovarian cancer [31] and chronic lymphocytic leukemia [32] patients. H-2RA have also been reported to block the production of histamine-induced suppressor factor (HSF) by H-2R + T suppressor cells, thereby augmenting Band T-cell function [33].…”

Section: Introductionmentioning

confidence: 99%

Effects of histamine type-2 receptor antagonists on indomethacin and IL-2 immunotherapy of metastasis

1993

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Histamine type-2 receptor antagonists (H-2RA) have been used chronically to prevent dyspepsia in cancer patients subjected to immunotherapy with chronic indomethacin (Indo) and intermittent IL-2 in our cancer centre. We tested the effects of these agents during immunotherapy of C3H/HeJ mice transplanted s.c. with 5 x 10(5) C3L5 mammary adenocarcinoma cells. Tumor-transplanted mice were divided into groups receiving: (1) Indo (14 micrograms/ml); (2) H-2RA, i.e. (a) ranitidine at 28.6 micrograms/ml (Ran-lo) or 143 micrograms/ml (Ran-hi), or (b) famotidine (Fam) at 4.3 micrograms/ml, or (c) cimetidine (Cim) at 107 micrograms/ml, all in the drinking water on days 5-24; (3) IL-2 (1.5 x 10(3) Cetus U i.p. every 8 h on days 10-14 and 20-24); (4) combinations of H-2RA + Indo; or (5) combinations of H-2RA + Indo + IL-2. Animals were killed on day 24 for examination of primary s.c. tumor growth, secondary lung metastasis and splenocyte cytotoxicity against YAC-1 lymphoma cells (51Cr release assay). Results revealed: (1) primary tumor growth was reduced in mice treated with Fam + Indo, Indo + IL-2 and any of the H-2RA + Indo + IL-2 (no difference observed within the last two groups); (2) lung metastases decreased in mice treated with IL-2 alone, Indo + IL-2, and Indo + IL-2 + Ran-hi; (3) splenic cytotoxicity was suppressed in tumor-bearing controls, with partial restoration seen in Ran (both doses), Ran-lo + Indo, Ran-lo + Indo + IL-2, and Cim + Indo + IL-2 treated groups. Nearly complete restoration was seen in Cim, Cim + Indo, Indo + IL-2, Ran-hi + Indo + IL-2, and Fam + Indo + IL-2 groups. Thus, addition of H-2RA did not alter the overall therapeutic efficacy of the standard Indo + IL-2 tumor immunotherapy.

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“…A meta-analysis of a number of studies has also failed to demonstrate survival benefits with conventional cytotoxic agents (Hermans et al, 1993). The H 2 -receptor antagonist cimetidine is well tolerated, anecdotally linked to healing of malignant gastric ulcers and has been shown to inhibit suppressor T-lymphocyte function (Griswold et al, 1984;Kikuchi et al, 1986), leading to suggestions that it could have a useful role as an anticancer agent. We have failed to replicate the findings of Tonneson et al (1988), who reported median survival to be improved from 316 days in placebo recipients to 450 days in those given cimetidine 400 mg twice daily, with a corresponding improvement in relative survival rates from 28% to 45% at 1 year.…”

Section: mentioning

confidence: 99%

“…The postulated mechanisms of action are mediated by H 2 -receptor blockade of suppressor T-lymphocytes, leading to their functional inhibition and stimulation of natural killer cell activity (Griswold et al, 1984;Kikuchi et al, 1986) and antagonism of histamine-stimulated growth (Watson et al, 1993). Tonnesen et al (1988) conducted a randomized trial and reported that cimetidine appeared to improve survival in gastric cancer patients.…”

mentioning

confidence: 99%

Prospective, double-blind, placebo-controlled randomized trial of cimetidine in gastric cancer

Langman¹,

Dunn

Whiting

et al. 1999

Br J Cancer

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Summary 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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Augmented natural killer activity in ovarian cancer patients treated with cimetidine

Cited by 25 publications

References 16 publications

Cisplatin-based polychemotherapy reduces the natural cytotoxicity of peripheral blood mononuclear cells in patients with advanced ovarian carcinoma and their in vitro responsiveness to interleukin-12 incubation

Cisplatin-based polychemotherapy reduces the natural cytotoxicity of peripheral blood mononuclear cells in patients with advanced ovarian carcinoma and their in vitro responsiveness to interleukin-12 incubation

Effects of histamine type-2 receptor antagonists on indomethacin and IL-2 immunotherapy of metastasis

Prospective, double-blind, placebo-controlled randomized trial of cimetidine in gastric cancer

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