Cimetidine (CIM) is a histamine H(2)-receptor antagonist in the identical class as ranitidine, famotidine, and nizatidine. Intensifying anti-tumour cell-mediated responses, cimetidine obstructs histamine’s ability to stimulate suppressor T lymphocyte action and inhibit natural killer (NK) cell action and interleukin-2 production. Cimetidine may also hinder tumor growth by repressing histamine’s growth-factor activity and preventing histamine-induced stimulation of vascular endothelial maturity factor (VEGF), a pro-angiogenic growth factor.
DOSAGE
Oral CIM is obtainable in tablet form and liquid suspension; oral cimetidine can also be used intravenously. Tablets are usually available in 200 mg, 400 mg, and 800 mg doses. For gastric or duodenal ulcer treatment, the adult dosage ranges between 800 mg and 1600 mg a day, either as separate or divided doses during the day, for 4–8 weeks. For reflux oesophagitis, the quantity is 400 mg four times a day for 4–8 weeks. CIM is also used for keeping therapy of gastric ulcers and short bowel syndrome at an everyday dose of 400 mg, with a long-term treatment continuing to greater than ten years in some cases.
TOXICITY
CIM has weak toxicity, with the most typical side effects being headache, dizziness, diarrhea, and rash. Uncommon side effects include gynecomastia, reversible impotence (mainly reported in patients receiving substantial doses, for example, in the therapy of Zollinger-Ellison Syndrome), and, very seldom, galactorrhoea. Infrequently, CIM has also been linked with reversible leukopenia and thrombocytopenia, effects that may be especially necessary to follow for cancer patients who may be enduring chemotherapy. CIM is contraindicated during gestation. Children above the age of one may use oral CIM at 25–30 mg/kg body weight per day in split doses. For children below the age of one, an amount of 20 mg/kg body weight per day in split doses has been used.
MECHANISM OF ACTION
The anti-tumor action of cimetidine has been proved to be due to four different mechanisms:
- Anti-proliferative activity on cancer cells
- Immunomodulatory effects
- Effects on cell adhesion
- Anti-angiogenic action
In vitro and in vivo studies, it has been confirmed that many tumor types display the histamine-synthesizing enzyme L-histidine decarboxylase (HDC) and that tumors can emit high histamine levels in a paracrine or autocrine manner. Histamine is highly pleiotropic, with various functions concerning inflammatory immune response, gastric acid release, and action as a neurotransmitter. These different physiological actions are mediated by four histamine receptors, of which H2 and H4 are associated with cancer cell propagation, invasion, and angiogenesis.
Histamine has various effects on innate and adaptive immune responses, interfered with by the four histamine receptors (H1–H4). Concerning cancer, histamine is correlated with an immunosuppressive tumor microenvironment, involving an increment in CD4+CD25+ regulatory T cell (Treg) activity, the diminished antigen-presenting activity of dendritic cells (DC), lessened NK-cell activity and improved myeloid-derived suppressor cell (MDSC) action.
CIM has been proved to have an inhibitory impact on cancer cell adhesion to endothelial cells free of its H2RA activity. A monolayer assay investigated the adhesion of HT-29 colorectal cancer cells to human umbilical vein endothelial cells for CIM and two other H2RAs (famotidine and ranitidine). While CIM inhibited adhesion in a dose-dependent manner, the other H2RAs did not affect it. CIM dose-dependently lessened the incidence of HT-29 liver metastases in a nude mouse model, suppressing it entirely at the highest dose (200 mg/kg/day). The interaction mediated cell adhesion between tumor sialyl Lewis antigens and E-selectin expressed on the endothelium.
The ultimate mechanism of action that has been investigated concerning the anti-cancer activity of CIM is the effect it has on tumor neo-angiogenesis. Ghosh et al. reviewed the role of histamine in the production of vascular endothelial growth factor (VEGF) in carrageenin-induced granulation tissue in rats. They found that the H2 receptor mediated it and that CIM reversed the upregulation of VEGF caused by histamine. Research comparing CIM and roxatidine (another H2RA) found that both drugs significantly reduced colon 38 tumor implants in C57BL /6 mice syngeneic mice. This inhibition was related to decreased expression of VEGF and reduced micro-vessel density in the implanted tumors. In addition, there is also proof that the anti-angiogenic effect of CIM administration may also be linked to a reduced appearance of platelet-derived endothelial growth factor (PDECGF) and VEGF in mouse and rat models of bladder cancer.
COLORECTAL CANCER
Based on initial in vitro and in vivo results, Adams and coworkers studied the use of perioperative CIM in patients bearing surgical resection of colorectal cancer. Control patients exhibited significant drops in lymphocyte proliferation and cell-mediated immunity. In opposition, patients dosed with oral CIM at a dose of 400 mg twice a day for at least five preoperative days, then intravenously for two postoperative days, revealed no significant falls in either lymphocyte propagation or cell-mediated immunity, symbolizing that CIM helped decrease postoperative immunosuppression following resection. There was some evidence that this variation could provide some clinical advantage in a follow-up that looked at the durability of three years in two subsequent reports, which noted that with a median follow-up at 30 months, the estimated three-year survival was 93% for cimetidine treated patients and 59% for controls.
MELANOMA
The most prime clinical evidence of an effect of the cimetidine on melanoma was in a group of three cases of recurrent malignant melanoma being handled with coumarin (at a dose of 100 mg per day). Oral CIM was commenced at a dose of 1000 mg every day when these patients no longer responded to coumarin therapy. In these cases, there was accelerated regression of various lesions and a corresponding and long-lasting development in physical condition. In one other case, the recurrent disease was managed with a lower dose of coumarin (25 mg) and cimetidine (1000 mg), but the condition increased, and the patient died soon after. This patient had not beforehand been treated with coumarin.
OTHER CANCERS
In pancreatic cancer, a recently published case report of the activity of the anti-angiogenic agent TL-118 introduces CIM as one of four drugs that make up the combination factor. In this case report, a 75-year older woman with radiologically verified inoperable pancreatic cancer has been managed with TL-118 and gemcitabine and has presented a long-lasting (16 months) progression-free survival. Therapy interruption associated with an increment of tumor marker CA 19-9, and resumption of therapy decreased levels of this marker.
An ancient trial looked at the combination of CIM and coumarin in metastatic prostate cancer, using the equivalent protocol as that for melanoma and RCC. Whilst the trial published no actual responses in the fourteen patients in the trial, three patients underwent a notable reduction in discomfort from bone metastases. They reduced analgesic use that persisted until condition progression at 3, 5.5+, and 9 months.
A short trial in 28 advanced serous ovarian cancer patients found that standard platinum-based chemotherapies expanded with cimetidine at a dose of 800 mg/day, beginning two weeks ere surgery and maintaining synchronously with chemotherapy showed statistically vital improvements in overall survival as opposed to platinum-based chemotherapy only.
