Perioperative cimetidine administration promotes peripheral blood lymphocytes and tumor infiltrating lymphocytes in patients with gastrointestinal cancer: Results of a randomized controlled clinical trial

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 CD 3 , CD 4 , CD 8 and CD 57 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 CD 3 and CD 20 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.

Anti-tumor effects of cimetidine on hepatocellular carcinomas in diethylnitrosamine-treated rats

“…Cimetidine has demonstrated immunomodulatory effects in a number of studies (32)(33)(34)(35)(36), while histamine has been shown to have immunosuppressive effects (37,38). These results suggest that the effect of cimetidine on immunity is mediated by blocking the immunosuppressive effect of histamine via the H 2 receptor.…”

The impact of anti-inflammatory agents on the outcome of patients with colorectal cancer

“…Similarly, the exaggerated post-operative immune suppression experienced in patients with CRC is in part mediated by histamine release (9). The use of H2RAs has been shown to abrogate tumour-associated systemic immune suppression [ Table 3], with restoration of circulating levels and activity of T-lymphocyte and NK cell subsets (116), potentially via augmentation of IL-2 and interferon activity.…”

“…Impaired cell-mediated immunity is common in cancer patients (8). Particularly in patients undergoing surgical resection of CRC, that is recognised to attenuate post-operative cell-mediated immunity (9), this may be an important mechanism by which disseminated or shed tumour cells evade effective immunosurveillance and establish de novo metastases (10)(11)(12). Furthermore, the presence of a systemic inflammatory response has been associated with a poorer response to chemotherapeutic agents and an increased risk of toxicity (13).…”

Cimetidine, an unexpected anti-tumor agent, and its potential for the treatment of glioblastoma (review)

“…Gastric cancer patients also have higher levels of suppressor lymphocyte activity when compared to normal controls, and these levels are restored to normal with CIM treatment (42). In a controlled randomized clinical trial, Lin et al (43) recently showed that pre-operative CIM administration at the dose of 400 mg/day promoted peripheral blood lymphocytes and tumor infiltrating lymphocytes in patients with gastrointestinal cancer.…”