Major Research Findings

Cyclophosphamide injection has been shown to have a variety of effects in mouse models. For example, 17 found that cyclophosphamide injection is useful for safety evaluation of new probiotics, and showed that there is no toxicity even in immunosuppressed mice. Also, 12 showed that cyclophosphamide injection is useful for safety evaluation of new Bacteroides fragilis strains, and that there were no adverse effects even in immunosuppressed mice. These studies suggest that cyclophosphamide injection is useful for safety evaluation of new probiotics.

On the other hand, 1 showed that cyclophosphamide injection can enhance immunotherapy in mice with tumors. Cyclophosphamide injection has been shown to activate NK cells and enhance anti-tumor effects.

Also, 14 found that cyclophosphamide injection can be used as a model of premature ovarian failure in mice, and that activation of mTOR (mammalian target of rapamycin) in ovarian tissue may contribute to the abnormal accumulation of MDSCs (myeloid-derived suppressor cells).

These studies suggest that cyclophosphamide injection can affect various immune cells. Further, showed that delayed hypersensitivity and antibody production vary depending on the timing and dose of cyclophosphamide injection. This study suggests that the effects of cyclophosphamide injection may vary significantly depending on the timing and amount of administration.

4 showed that protocatechuic acid has an immunomodulatory effect on brain injury induced by cyclophosphamide chemotherapy in rats. Protocatechuic acid has been shown to protect against brain injury by modulating the inflammasome NLRP3 and SIRT1. This study suggests a new therapeutic strategy for mitigating the side effects of cyclophosphamide injection.

3 showed that lignin derivative BP-C2 has antigenotoxic and antimutagenic effects against dioxidine and cyclophosphamide in vivo in murine cells. BP-C2 has been shown to suppress DNA damage and reduce the number of chromosomal aberrations induced by cyclophosphamide and dioxidine. This study suggests that BP-C2 is a promising new therapeutic strategy for mitigating the side effects of chemotherapy drugs such as cyclophosphamide.

22 showed that cyclophosphamide injection induces cashmere shedding in cashmere goats. Cyclophosphamide injection has been shown to reduce erythrocyte count and hemoglobin concentration in cashmere goats, but it has no effect on cashmere length and significantly increases cashmere yield. This study suggests that cyclophosphamide injection is a promising new method for inducing cashmere shedding in cashmere goats.

19 showed that cyclophosphamide injection affects appetitive qualities and detection thresholds of salt taste in mice. Cyclophosphamide injection has been shown to reduce salt taste preference and increase detection thresholds. This study suggests that cyclophosphamide injection may affect taste.

6 showed that trypsin increases contractile responses of detrusor smooth muscle in a rat model of interstitial cystitis/bladder pain syndrome (IC/BPS). Trypsin has been shown to increase contractile responses of detrusor smooth muscle by activating PAR2 and intracellular calcium release pathways. This study suggests that trypsin may play an important role in the pathophysiology of IC/BPS.

9 examined the role of increased vascular permeability in chemotherapy-induced alopecia using in vivo imaging of the hair follicular microenvironment in mice. Cyclophosphamide injection has been shown to reduce hair bulb size, decrease blood vessel density around the hair follicle, and increase vascular permeability. This study suggests that increased vascular permeability may be one of the causes of chemotherapy-induced alopecia.

11 examined the permeability of intestinal and blood-tissue barriers in rats for Evans blue dye under conditions of acute intoxication with cyclophosphamide. Cyclophosphamide injection has been shown to increase the accumulation of Evans blue dye in the blood, brain, lung, liver, kidney, and ileum of rats. This study suggests that cyclophosphamide injection may damage the intestinal and lung-blood barriers, allowing biologically active substances from the small intestine, gastrointestinal chyme, and lungs to enter the blood.

21 screened for the optimal dose of benzene and cyclophosphamide using an orthogonal design for establishment of New Zealand rabbit models of aplastic anemia.

13 investigated the urodynamic effects of intravesical administration of bovine adrenal medulla 8-22 (BAM8-22), a selective rat sensory neuron-specific receptor 1 agonist, on the micturition reflex in normal rats and rats with cyclophosphamide-induced bladder overactivity.

5 reports the case of a 67-year-old Japanese woman who developed IgAV (IgA vasculitis) after receiving the second dose of the Pfizer-BioNTech COVID-19 vaccine. This patient developed purpura on her extremities and trunk after vaccination, followed by acute kidney injury and nephrotic syndrome. The kidney biopsy revealed diffuse mesangial and endocapillary glomerulonephritis with necrotizing crescent formation accompanied by IgA deposition. This case suggests the possibility of severe glomerulonephritis with IgAV developing after COVID-19 vaccination.

20 showed that USC-087 protects Syrian hamsters against lethal challenge with human species C adenoviruses. USC-087 has been shown to be highly effective against multiple human adenovirus types in cell culture. USC-087 is also effective against AdV-C6 in a model of immunosuppressed Syrian hamsters. In this model, hamsters are immunosuppressed by treatment with high-dose cyclophosphamide. Intravenous injection of AdV-C6 (or AdV-C5) leads to a disseminated infection that resembles the disease seen in humans, including death. This study examined the efficacy of orally administered USC-087 against the median lethal dose of intravenously administered AdV-C6. USC-087 completely prevented or significantly decreased mortality when administered up to 4 days post challenge. USC-087 also prevented or significantly decreased liver damage caused by AdV-C6 infection and suppressed virus replication even when administered 4 days post challenge. These results suggest that USC-087 is a promising candidate for drug development against HAdV infections.

15 examined the effects of co-transplantation of hemopoietic and mesenchymal hemopoietic stem cells on the rate of bone marrow hemopoiesis recovery in mice with cytostatic aplasia caused by a single injection of cyclophosphamide. Co-transplantation of mesenchymal stem cells and hemopoietic stem cells has been shown to accelerate recovery from bone marrow suppression induced by cyclophosphamide. This study suggests the possibility of promoting recovery from bone marrow suppression induced by chemotherapy by co-transplantation of hemopoietic and mesenchymal hemopoietic stem cells.

8 examined the effects of N-acetylcysteine on cyclophosphamide-induced immunosuppression, liver injury, and oxidative stress in miniature pigs. Miniature pigs were used as an experimental model to evaluate the effects of N-acetylcysteine treatment on immune reactions, liver injury, and oxidative stress after cyclophosphamide challenge. N-acetylcysteine has been shown to reduce immunosuppression, liver injury, and oxidative stress in miniature pigs challenged with cyclophosphamide. This study suggests that N-acetylcysteine is a promising new therapy for mitigating the side effects of cyclophosphamide.

18 examined the ameliorative effect of silymarin against linezolid-induced hepatotoxicity in methicillin-resistant Staphylococcus aureus (MRSA)-infected Wistar rats. Linezolid is a good choice for eradicating MRSA infections, but its use is limited due to linezolid-induced hepatotoxicity, myelosuppression, and lactic acidosis. Silymarin has been shown to reduce liver damage induced by linezolid. This study suggests that silymarin is a promising new therapy for mitigating the side effects of linezolid.

16 showed that cyclophosphamide pulse therapy normalizes vascular abnormalities in a mouse model of systemic sclerosis (SSc) vasculopathy. Cyclophosphamide pulse therapy is a standard treatment for SSc-related interstitial lung disease and has a disease-modifying effect on SSc vasculopathy, such as promoting microvascular de-remodeling. This study used endothelial cell-specific Fli1 knockout mice, which mimic the functional and structural vascular abnormalities characteristic of SSc, to investigate the molecular mechanism by which cyclophosphamide mitigates SSc vasculopathy. Biweekly cyclophosphamide injection improved vascular permeability and structural abnormalities in endothelial cell-specific Fli1 knockout mice within 2 weeks and 3 months, respectively. In endothelial cell-specific Fli1 knockout mice, a single dose of cyclophosphamide was sufficient to normalize the decreased expression of α-smooth muscle actin in dermal blood vessels and improve impaired neovascularization in skin-embedded Matrigel plugs. Under the same conditions, the decreased expression of vascular endothelial cadherin, platelet-derived growth factor B, S1P₁, and CCN1 (molecules associated with angiogenesis and/or vasculogenesis) was reversed along with the reversal of endothelial Fli1 expression. In SSc patients, serum CCN1 levels were significantly increased after intravenous cyclophosphamide pulse. Taken together, these results indicate that cyclophosphamide improves Fli1 deficiency-dependent vascular changes by normalizing the expression of angiogenesis- and vasculogenesis-related molecules and endothelial Fli1, which may help to explain the beneficial effect of cyclophosphamide on SSc vasculopathy.

7 performed single-cell RNA sequencing on individual primordial follicle oocytes 12 hours after a single cyclophosphamide injection using a human ovarian xenograft model. RNA sequencing revealed 190 differentially expressed genes between cyclophosphamide- and vehicle-exposed oocytes. Ingenuity Pathway Analysis predicted a significant decrease in the expression of anti-apoptotic pro-Akt PECAM1 (p = 2.13E-09), IKBKE (p = 0.0001), and ANGPT1 (p = 0.003) and reduced activation of PI3K/PTEN/Akt after cyclophosphamide. qRT-PCR and immunostaining confirmed that cyclophosphamide did not change the expression of Akt (p = 0.9), rpS6 (p = 0.3), Foxo3a (p = 0.12), and anti-apoptotic Bcl2 (p = 0.17), nor affect their phosphorylation status in primordial follicle oocytes. DNA damage by γH2AX (p = 0.0002) and apoptosis by active-caspase-3 (p = 0.0001) staining were significantly increased in primordial follicles but not in growing follicles 12 hours after chemotherapy. These data support that the mechanism of acute follicle loss by cyclophosphamide is via apoptosis rather than growth activation of primordial follicle oocytes in the human ovary.

10 analyzed the proteome of the thymus and spleen in mice that were immunosuppressed by cyclophosphamide injection. The study found that 10-hydroxydec-2-enoic acid (10-HDA), a unique component of royal jelly, could enhance immunity in mice. 10-HDA supplementation rescued the weight of the body, thymus, and spleen in cyclophosphamide-induced mice, indicating its potential role in immuno-organ protection. The enhanced activity of pathways associated with DNA/RNA/protein activities in the thymus may be critical for T-lymphocyte proliferation/differentiation and cytotoxicity. In the spleen, the induced pathways involved in DNA/RNA/protein activities and cell proliferative stimulation suggest their vital role in B-lymphocyte affinity maturation, antigen presentation, and macrophage activity. Up-regulated proteins highly connected in networks modulated by 10-HDA indicate that the mice may evolve tactics to respond to immuno-organ impairment by activating critical physiological processes. This study constitutes a proof-of-concept that 10-HDA is a potential agent to improve immunity in the thymus and spleen and offers a new venue for applying natural products to the therapy for hypoimmunity.

2 showed that niclosamide, a STAT3 inhibitor, modulates the cellular and humoral immune response in Balb/c mice. STAT3 plays an important role in immune responses. Niclosamide has been shown to inhibit the proliferation of spleen cells in Balb/c mice, modulate cytokine production, and suppress antibody production. This study suggests that niclosamide may regulate the immune system.

Benefits and Risks

Benefits Summary

Cyclophosphamide injection is used to treat a variety of diseases, especially cancer, immunosuppression, transplantation, and autoimmune diseases. In addition, 1 showed that cyclophosphamide injection can enhance immunotherapy in mice with tumors. Cyclophosphamide injection has been shown to activate NK cells and enhance anti-tumor effects. Further, 16 showed that cyclophosphamide pulse therapy normalizes vascular abnormalities in a mouse model of systemic sclerosis (SSc) vasculopathy. Cyclophosphamide pulse therapy is a standard treatment for SSc-related interstitial lung disease and has a disease-modifying effect on SSc vasculopathy, such as promoting microvascular de-remodeling.

Risks Summary

Cyclophosphamide injection can cause a variety of side effects. The most common side effects are nausea, vomiting, hair loss, bone marrow suppression, and an increased risk of infection. It can also affect the liver and kidneys. Cyclophosphamide injection should not be used in pregnant or breastfeeding women. Furthermore, 14 showed that cyclophosphamide injection can be used as a model of premature ovarian failure in mice, and that activation of mTOR (mammalian target of rapamycin) in ovarian tissue may contribute to the abnormal accumulation of MDSCs (myeloid-derived suppressor cells). Also, 11 showed that cyclophosphamide injection increases the accumulation of Evans blue dye in the blood, brain, lung, liver, kidney, and ileum of rats. These studies suggest that cyclophosphamide injection may have adverse effects on various organs.

Comparison of Studies

Commonalities

These studies suggest that cyclophosphamide injection affects the immune system. In particular, cyclophosphamide injection may affect immunosuppression, cytotoxicity, angiogenesis, cell proliferation, etc. These studies also suggest that cyclophosphamide injection is useful for treating a variety of diseases, such as cancer, immunosuppression, transplantation, and autoimmune diseases.

Differences

These studies vary in the administration method, dosage, effects, and target diseases of cyclophosphamide injection. For example, 17 and 12 use cyclophosphamide injection for safety evaluation of new probiotics, whereas 1 uses it to enhance immunotherapy in mice with tumors. Thus, cyclophosphamide injection is used for various purposes.

Consistency and Contradictions of Results

The results of these studies suggest that cyclophosphamide injection can have a variety of effects on the immune system. However, the specific effects of cyclophosphamide injection vary greatly depending on the administration method, dosage, and target disease. Therefore, further research is needed to accurately assess the effects of cyclophosphamide injection.

Implications for Everyday Life

Cyclophosphamide injection is used to treat a variety of diseases, but it can cause many side effects. Therefore, cyclophosphamide injection should be used properly as instructed by a doctor. It is important to consult a doctor before using cyclophosphamide injection and to inform them of your medical condition, past medical history, and any medications you are taking.

Limitations of Current Research

These studies were mainly conducted using animal models such as mice and rats. Therefore, it is unknown whether the results of these studies can be directly applied to humans. These studies examined the effects of cyclophosphamide injection from various aspects, but there are still many unknown aspects of the mechanism of action of cyclophosphamide injection. Furthermore, the development of new therapies to mitigate the side effects of cyclophosphamide injection is a future challenge.

Future Research Directions

Clinical studies involving humans are needed to investigate the effects of cyclophosphamide injection in more detail. Research to clarify the mechanism of action of cyclophosphamide injection is also important. Furthermore, developing new therapies to mitigate the side effects of cyclophosphamide injection is an important direction for future research.

Conclusion

Cyclophosphamide injection is used to treat a variety of diseases. However, it can cause many side effects. Therefore, cyclophosphamide injection should be used properly as instructed by a doctor. Further research is needed to investigate the effects of cyclophosphamide injection in more detail.