Redefining
Cancer
Treatment
Redefining
Cancer
Treatment
Cimetidine has been classified as a prescription only medicine at higher doses in the UK. Other countries policies may differ. Check with your local healthcare regulator. It’s price ranges from £7-58 for the 200mg tablets with a specified used of 14 days only unless under medical supervision.
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Cimetidine, a histamine H2-receptor antagonist traditionally used for gastric acid suppression, has demonstrated notable anticancer properties through multiple mechanisms. Emerging evidence suggests its potential as an adjuvant therapy in colorectal, gastric, and other cancers, particularly by targeting metastasis and modulating immune responses.
Metastasis Inhibition via E-Selectin Blockade
Cimetidine disrupts cancer cell adhesion to blood vessels by suppressing endothelial E-selectin expression58. This prevents tumour cells expressing sialyl Lewis X/A antigens from anchoring to vascular walls, reducing metastatic spread16. In colorectal cancer patients with high sialyl Lewis antigen levels, cimetidine improved 10-year survival to 95.5% vs. 35.1% in controls68.
Immunomodulation
The drug enhances tumour-infiltrating lymphocytes (TILs) and peripheral CD3+/CD4+ T cells, boosting immune surveillance23. A 1994 trial noted a 41% → 7% reduction in 3-year mortality for colorectal cancer patients after just 7 days of perioperative cimetidine2.
Antiangiogenic Effects
Cimetidine reduces VEGF and PDECGF expression, impairing vascular tube formation in preclinical models47. This complements its direct antiproliferative action on histamine-driven tumour growth49.
Colorectal Cancer:
A landmark 10-year study showed 84.6% survival with cimetidine + 5-FU vs. 49.8% with 5-FU alone6. Benefits were strongest in advanced (Dukes C) cases (84.6% vs. 23.1% survival)6.
Gastric Cancer:
400 mg twice daily for 2 years extended survival in stage II-IV patients29.
Synergy with Chemotherapy:
Combined with temozolomide, cimetidine prolonged survival in glioblastoma models4.
Typical protocols include:
800 mg/day + 5-FU for 12 months post-colorectal cancer surgery16
400 mg twice daily for 2 years in gastric cancer2
Short-term perioperative use (5–7 days) to reduce metastasis risk28
While preclinical data support cimetidine’s broad anticancer potential, clinical results vary by cancer type and biomarker status310. Large-scale RCTs are needed to validate its role alongside modern therapies, particularly in sialyl Lewis antigen-positive tumors39. Its excellent safety profile and low cost make it a compelling candidate for repurposing10.
For metabolic therapy applications, cimetidine’s dual action on immune function and metastasis pathways positions it as a multifunctional adjuvant, though patient stratification by molecular biomarkers is crucial for optimal outcomes.
Cimetidine’s anticancer dosing protocols have been studied in multiple clinical trials, demonstrating safety and efficacy within specific parameters.
Key findings from research include:
Colorectal Cancer
Gastric Cancer
400 mg twice daily for 2 years improved survival in stage II-IV patients3.
Maximum daily limit: 2.4 g (2400 mg)46, though anticancer studies rarely exceed 800-1600 mg/day.
Renal adjustment:
No dose-limiting toxicity reported in trials using 800 mg/day for 1 year15.
Long-term safety data exist for up to 6 years of continuous use in non-cancer contexts4.
For metabolic therapy applications, the 800 mg/day regimen (with 5-FU) has the strongest colorectal cancer evidence15, while 400 mg twice daily shows efficacy in gastric cancer and perioperative settings3. Doses should be adjusted for renal impairment and monitored in hepatic dysfunction24.
Brain Cancer, Colorectal Cancer, Gastrointestinal Stromal Tumor (GIST), Skin Cancer (including Melanoma)
Cimetidine is generally well-tolerated but may cause side effects ranging from mild gastrointestinal symptoms to rare serious complications.
Below is a structured analysis of its safety profile:
Gastrointestinal: Diarrhoea, nausea, vomiting, constipation, flatulence2568
Musculoskeletal: Reversible myalgia (muscle pain) or arthralgia (joint pain)6
These typically resolve as the body adjusts to treatment and rarely require discontinuation58.
Central Nervous System (CNS) Effects:
Allergic Reactions:
Hematologic:
Endocrine:
Hepatic/Renal:
Cancer Risk: An initial study noted elevated risks for gastric, pancreatic, and colorectal cancers in the first year of use, though this likely reflects misdiagnosed malignancies rather than drug-induced carcinogenesis1.
Drug Interactions: CYP3A4 inhibition may alter metabolism of chemotherapy agents (e.g., tamoxifen, fluorouracil)7.
Safety in Trials: No dose-limiting toxicity reported at 800 mg/day for 12 months in colorectal cancer studies7.
Monitoring: Regular CBC and renal/liver function tests advised for patients on prolonged regimens6.
While cimetidine’s safety profile is favourable compared to many chemotherapies, its endocrine and CNS effects warrant vigilance, particularly in vulnerable populations. The drug’s low cost and tolerability support its repurposing potential, but biomarker-guided use (e.g., sialyl Lewis antigen status) may optimise risk-benefit ratios7.
Cimetidine has been extensively tested in combination therapies across multiple cancer types, demonstrating synergistic effects in both preclinical and clinical settings. Key combinations supported by trial evidence include:
5-FU/Leucovorin:
Perioperative Protocol:
800 mg twice daily for 5 weeks (starting 1 week pre-surgery) reduced postoperative cytokine spikes and improved disease-free survival5.
Chemotherapy Adjuvant:
400 mg twice daily for 2 years combined with standard regimens extended survival in stage II-IV patients2.
Platinum-Based Chemotherapy:
800 mg/day cimetidine combined with carboplatin/paclitaxel improved survival in advanced serous ovarian carcinoma (FIGO III/IV), particularly in COX-2-overexpressing tumors4.
Immunotherapy Combo:
Single-Agent vs. PALA/L-Alanosine:
Cimetidine alone (300 mg four times daily) achieved 1 CR and 2 PR in metastatic melanoma, outperforming the combination PALA/L-alanosine (1 PR)1.
TL-118 Multi-Targeted Therapy:
Oral combination of cimetidine + low-dose cyclophosphamide + diclofenac + sulfasalazine is being tested in phase II trials for metastatic pancreatic and prostate cancers5.
Chemotherapy Enhancement:
Immune Modulation:
ACTRN12609000769280: Perioperative cimetidine in colorectal cancer (2-year disease-free survival data pending)5.
NCT01509911: TL-118 + gemcitabine in pancreatic cancer (disease control rate at 16 weeks)5.
Cimetidine’s low toxicity profile and multi-targeted mechanisms (E-selectin inhibition, immune modulation) make it a versatile partner in combination therapies, particularly for gastrointestinal and immunogenic tumours.
US National Library of Medicine research on Cimetidine
Cimetidine’s impact on quality of life (QoL) in cancer therapy involves a balance between its survival benefits and manageable side effects, with outcomes dependent on patient selection and treatment context:
Survival Improvement:
In colorectal cancer patients with high sialyl Lewis X/A antigen expression, cimetidine (800 mg/day + 5-FU) achieved 95.5% 10-year survival vs. 35.1% in controls15. Improved survival often correlates with better long-term QoL.
Perioperative use (5–7 days) reduced 3-year mortality from 41% to 7% in colorectal cancer18, potentially minimising prolonged treatment burdens.
Tolerability:
Immunomodulation:
Common Side Effects:
Hormonal Effects:
Long-term high-dose use (e.g., ≥1,000 mg/day) may cause gynecomastia (up to 20% in some studies) or sexual dysfunction7, impacting QoL if unresolved.
Variable Efficacy:
| Factor | Impact on QoL |
|---|---|
| Biomarker status | High sialyl Lewis X/A expression → Strong survival benefit with minimal side effects15. |
| Cancer stage | Advanced (Dukes C) colorectal cancer → Significant survival gains outweigh risks18. |
| Treatment duration | Short perioperative courses (5–7 days) → Lower cumulative toxicity1. |
| Comorbidities | Renal/hepatic impairment → Requires dose adjustments to avoid CNS or metabolic side effects3610. |
For biomarker-selected patients (e.g., high sialyl Lewis antigens in colorectal cancer), cimetidine’s survival benefits and mild side effect profile likely result in a net positive QoL impact. However, in non-responsive cancers or patients with low biomarker expression, the modest side effects and lack of efficacy may lead to a neutral or negative QoL balance. Personalised dosing, monitoring, and biomarker stratification are critical to optimising outcomes.
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Cimetidine remains widely accessible globally through multiple channels, though availability varies by region and formulation. Here’s a structured analysis of its current access and availability:
United Kingdom:
United States:
Low-dose formulations:
Shortage Context:
Australia:
No active shortage reports for cimetidine, though other drugs (e.g., tenecteplase) face supply issues3.
| Region | Prescription | OTC | Online Retail |
|---|---|---|---|
| UK | NHS/private clinics | Limited (low-dose Tagamet HB) | Pharmacy Planet UK7 |
| US | Clinics/hospitals | Major retailers (e.g., CVS) | Not typically sold online |
| EU | Varies by country | Available in pharmacies | EU-based online pharmacies |
| Form | Source | Price |
|---|---|---|
| 400 mg (60 tablets) | NHS UK | £7.262 |
| 800 mg (30 tablets) | Pharmacy Planet UK | £46.00 (generic) – £53.00 (Tagamet)7 |
| 200 mg (60 tablets) | US Retail | $23.86–$57.941 |
UK Formulary Guidance:
Cimetidine is restricted to cases where PPIs fail or are unsuitable (e.g., biliary reflux post-pancreatic surgery)6.
Renal/Hepatic Impairment:
Requires dose adjustments (e.g., 200 mg twice daily if CrCl <30 mL/min)1.
Supply Resilience:
No imminent shortages reported, but reliance on Chinese API suppliers (e.g., Xi’an Xinlu Biotechnology) introduces potential volatility1.
Cimetidine’s accessibility is robust in most regions, with cost-effective NHS options in the UK and OTC availability for symptom relief.
Prescription requirements for higher doses ensure supervised use in complex cases.
Cimetidine demonstrates optimal therapeutic outcomes in specific colorectal cancer patient subgroups, particularly when stratified by biomarker status and disease stage:
Key Biomarker: Patients with tumours strongly expressing sialyl Lewis X and/or A antigens (ligands for E-selectin) show dramatic survival benefits.
Stage-Specific Efficacy:
Early-stage (Dukes A/B) benefits were less pronounced, though trends favoured cimetidine5.
Timing Advantage:
Immune Function:
Low Sialyl Lewis Antigen Tumours: Minimal survival improvement vs. controls5.
Late-Stage, High Tumour Burden: Reduced efficacy in metastatic RCC and heavily pretreated patients1.
| Factor | Optimal Patient Profile |
|---|---|
| Biomarker | High sialyl Lewis X/A expression |
| Stage | Dukes C colorectal cancer |
| Timing | Perioperative (pre-/post-surgery) |
| Immune Status | Preserved immune function |
Cimetidine’s efficacy is biomarker- and context-dependent, with the strongest evidence supporting its use in sialyl Lewis antigen-positive, advanced colorectal cancer patients undergoing curative resection. Immunological fitness further enhances therapeutic response156.
Cimetidine’s anticancer efficacy can be compromised by several resistance mechanisms, primarily tied to tumour biology and molecular interactions.
Here’s a breakdown of the key factors identified:
Impact: Tumours lacking these carbohydrate antigens show reduced response to cimetidine due to its inability to block E-selectin-mediated metastasis.
Evidence:
Colorectal cancer patients with low sialyl Lewis antigen expression had 35.1% 10-year survival vs. 95.5% in high-expression tumours treated with cimetidine15.
FOXP3 Deficiency:
Gastric cancer (GC) cells with low FOXP3 levels exhibit reduced sensitivity to cimetidine. IC50 values for cimetidine inversely correlate with FOXP3 expression (HGC27 > MKN45 > SGC7901)2.
STUB1 Inactivation:
Knockdown of STUB1 (an E3 ubiquitin ligase) rescues FOXP3 degradation, reversing cimetidine’s antitumor effects. PI3K/Akt pathway inhibitors block cimetidine-induced STUB1 upregulation2.
Alternative Signalling:
Cimetidine’s anti-angiogenic effects via VEGF/PDECGF suppression may be circumvented if tumours utilise histamine-independent angiogenesis pathways36.
COX-2 Pathway Activation:
In some colorectal cancers, VEGF expression is driven by H4 receptors, or COX-2, which cimetidine does not effectively inhibit6.
Neutrophil Infiltration:
Cimetidine attenuates anti-PD-1/PD-L1 efficacy by reducing CD3+/CD8+ T cells and M1 macrophages while increasing immunosuppressive neutrophils in CT26 colon cancer models7.
Mismatch Repair Status:
Proficient mismatch repair (pMMR) tumours show weaker synergy with immunotherapy when combined with cimetidine7.
H2 Receptor Irrelevance:
Cimetidine’s effects in glioblastoma and melanoma occur independently of H2 receptor activity. Tumours not reliant on histamine-driven proliferation are less responsive46.
| Resistance Factor | Mechanism | Cancer Type |
|---|---|---|
| Low sialyl Lewis antigens | Loss of E-selectin binding inhibition | Colorectal, Gastric |
| FOXP3/STUB1 deficiency | Failed proteasomal degradation of oncoproteins | Gastric |
| Immunosuppressive TME | Reduced T-cell infiltration | Colorectal (with immunotherapy) |
| Alternative angiogenic pathways | VEGF/PDECGF-independent vascularisation | Multiple cancers |
Cimetidine’s efficacy is highly context-dependent, emphasising the need for biomarker-driven patient selection (e.g., sialyl Lewis antigen status, FOXP3 levels). Resistance may arise from tumour adaptation or combinatorial therapy conflicts, warranting careful protocol design127.
Cimetidine has demonstrated promising anticancer effects in preclinical trials across various cancer types, with mechanisms spanning metastasis inhibition, immunomodulation, and synergy with chemotherapy.
Key findings from preclinical studies include:
Mechanism: Cimetidine downregulates endothelial E-selectin expression, blocking adhesion of tumour cells expressing sialyl Lewis X/A antigens. This prevents metastatic spread in colorectal and gastric cancers1368.
In Vivo Evidence:
Specificity: Effects were unique to cimetidine; other H2 antagonists (famotidine, ranitidine) showed no impact3.
Lymphocyte Infiltration:
Synergy with Chemotherapy:
Lung Adenocarcinoma:
Gastric Cancer:
Replication Issues:
Biomarker Dependence:
| Cancer Type | Model | Findings |
|---|---|---|
| Colorectal | Nude mice, cell lines | Reduced metastasis via E-selectin inhibition35 |
| Gastric | Endothelial cell assays | Blocked adhesion (40–60% reduction)68 |
| Lung | A549 xenografts | Tumour reduction (statistically variable)2 |
| Leukaemia | P-388 mouse model | Enhanced cyclophosphamide efficacy7 |
Combination Therapies: Synergy with razoxane (anti-angiogenic agent) and checkpoint inhibitors warrants exploration7.
Biomarker-Driven Models: Focus on sialyl Lewis X/A-positive tumours to optimise efficacy16.
Cimetidine’s preclinical profile supports its role as a multimodal anticancer agent, particularly in metastasis prevention. However, variability in study outcomes underscores the need for standardised models and biomarker stratification.
For clinical trial phases, visit clinicaltrials.gov.
Cimetidine’s anticancer efficacy is influenced by specific molecular and genetic factors, with key biomarkers identified across cancer types:
Impact: Tumours lacking these carbohydrate antigens show reduced response to cimetidine.
Evidence:
Colorectal cancer patients with low sialyl Lewis antigen expression had 35.1% 10-year survival vs. 95.5% in high-expression tumours treated with cimetidine1.
Mechanism: Cimetidine blocks E-selectin-mediated metastasis, which depends on sialyl Lewis antigen binding15.
Impact: Lower FOXP3 expression correlates with reduced cimetidine sensitivity in gastric cancer (GC).
Evidence:
Impact: Reduced STUB1 (E3 ubiquitin ligase) expression limits cimetidine’s ability to degrade FOXP3.
Evidence:
Conflict:
Immunosuppressive TME:
Cimetidine attenuated anti-PD-1/PD-L1 efficacy in CT26 colon cancer models by:
pMMR Status:
CT26 tumours (proficient mismatch repair) showed reduced immunotherapy synergy with cimetidine, though direct genetic links require validation7.
| Biomarker | Resistance Mechanism | Cancer Type |
|---|---|---|
| Low sialyl Lewis X/A | Loss of E-selectin binding inhibition | Colorectal |
| Low FOXP3/STUB1 | Impaired proteasomal degradation | Gastric |
| PI3K/Akt pathway mutations | Failed STUB1 upregulation | Gastric, Glioblastoma |
| Neutrophil-rich TME | Immunosuppression reversal | Colorectal (anti-PD-L1 combo) |
Cimetidine’s efficacy is highly context-dependent, emphasising the need for biomarker-driven patient selection. Tumours with low sialyl Lewis antigens, FOXP3/STUB1 deficiency, or immunosuppressive microenvironments are less likely to respond.
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